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    "result": {"data":{"article":{"manuscript":{"id":"c179d960-a96f-4e75-891f-e7ec632b42ce","submissionTypes":["new finding"],"citations":[],"doi":"10.17912/micropub.biology.002107","dbReferenceId":null,"pmcId":null,"pmId":null,"proteopedia":null,"reviewPanel":null,"species":["human","mouse"],"integrations":[],"corrections":null,"history":{"received":"2026-03-20T22:05:08.403Z","revisionReceived":"2026-04-21T21:21:52.688Z","accepted":"2026-04-23T16:51:13.507Z","published":"2026-04-26T23:15:05.832Z","indexed":"2026-05-10T23:15:05.832Z"},"versions":[{"id":"35f19c50-25ba-41dd-8828-e08826f94323","decision":"revise","abstract":"<p>Neurofibromatosis type 1 (NF1) and Neurofibromatosis type 2 (NF2) are both inherited tumor syndromes characterized by Schwann cell tumors.&nbsp; NF1 tumors harbor activated Ras/MEK/ERK, while NF2 tumors harbor activated mechanosignaling pathways, including Hippo/YAP-TAZ/TEAD.&nbsp; To test combinatorial strategies in tumor cell lines, we first screened a new-generation TEAD inhibitor, VT103, against 123 drugs and then validated the hits with pairwise titrations.&nbsp; VT103 consistently synergized with inhibitors of MEK (MEK: trametinib and selumetinib; SHP2:&nbsp; TNO155) and mTOR (everolimus).&nbsp; The highest synergy (SynergyFinder ZIP~65) was in the NF2 cell line SC4, with lower magnitudes in an NF1 cell line.</p>","acknowledgements":"<p>We thank Dr. David Schultz from the High Throughput Screening Core of the Perelman School of Medicine for helpful discussions. &nbsp;We thank Tracy Tang and Len Post from Vivace Therapeutics for TEAD inhibitors.  We thanks students in Chem 495 for helpful discussions.&nbsp;</p>","authors":[{"affiliations":["University of Pennsylvania","Harvard University, Cambridge, MA, US"],"departments":["Systems Pharmacology and Translational Therapeutics",""],"credit":["investigation","dataCuration","formalAnalysis"],"email":"yyang60@mgh.harvard.edu","firstName":"Yang","lastName":"Yang","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":"ORC ID 0000-0003-3801-681X"},{"affiliations":["University of Pennsylvania, Philadelphia, PA, US"],"departments":["Systems Pharmacology and Translational Therapeutics"],"credit":["investigation","dataCuration","formalAnalysis"],"email":"sharavana.gurunathan@pennmedicine.upenn.edu","firstName":"Sharavana","lastName":"Gurunathan","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":"0000-0001-9817-7282"},{"affiliations":["University of Pennsylvania, Philadelphia, PA, US"],"departments":["Systems Pharmacology and Translational Therapeutics "],"credit":["dataCuration","writing_reviewEditing"],"email":"shsch@seas.upenn.edu","firstName":"Shane","lastName":"Schechter","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":"0009-0007-8411-8864"},{"affiliations":["University of Pennsylvania, Philadelphia, PA, US"],"departments":["Systems Pharmacology and Translational Therapeutics"],"credit":["conceptualization","fundingAcquisition","project","writing_originalDraft"],"email":"jfield@upenn.edu","firstName":"Jeffrey","lastName":"Field","submittingAuthor":true,"correspondingAuthor":true,"equalContribution":false,"WBId":null,"orcid":"0000-0001-7161-7284"}],"awards":[],"conflictsOfInterest":"<p>The authors declare that there are no conflicts of interest present.</p>","dataTable":null,"extendedData":[],"funding":"<p>Supported by the AY GAPSA Provost Fellowship for Interdisciplinary Innovation, the Children’s Tumor Foundation (2019-05-004) and the DOD, (CDMRP NF180079).</p>","image":{"url":"https://portal.micropublication.org/uploads/3d640e39f76488a0ff638c2928ece78f.png"},"imageCaption":"<p>(A) Large-scale heatmap shows IC50 values for a compound panel in NF1 and NF2 lines ± 2 µM VT103. &nbsp;(B) Focused heatmap highlights agents with VT103-induced IC50 reductions. &nbsp;(C) Bar plots ranking ZIP synergy scores from 6×6 matrices in ST88-14 (NF1), SC4 (NF2), and HEI193 (NF2), respectively.</p>","imageTitle":"<p>NF1 and NF2 screening and synergy analyses</p>","methods":"<p></p>","reagents":"<p></p>","patternDescription":"<p><b>Description</b></p><p>Neurofibromatosis type 1 (NF1) and type 2 (NF2) are tumor predisposition syndromes driven by loss of function mutations in NF1 (neurofibromin) and NF2 (merlin), respectively. &nbsp;Patients with NF1 or NF2 develop nonmalignant tumors primarily in Schwann cells.&nbsp; NF1 patients develop neurofibromas while NF2 patients develop Schwannomas.&nbsp; About 10% of NF1 patients will develop malignant peripheral nerve sheet tumors (MPNST) from neurofibromas.&nbsp; NF1 and NF2 cell comparisons are useful in drug screens because they are both derived from Schwann cells but have distinct primary driver mutations.</p><p>&nbsp;</p><p>Neurofibromin is a RasGAP, so NF1 loss results in constitutive activation of RAS and its downstream signals through MEK/ERK and PI3K/mTOR.&nbsp; Several MEK inhibitors are FDA approved to treat NF1 neurofibromas (Anastasaki et al., 2022).&nbsp; Though MPNST cell models respond to MEK inhibitors, MPNST patients show little response to MEK inhibitors as single agents or in combination with mTOR inhibitors (de Blank et al., 2022; Gross et al., 2020; Kim et al., 2026).&nbsp;</p><p>&nbsp;</p><p>Merlin is a cytoskeletal protein and its loss in NF2 tumors activates several mechanosignaling pathways, including PAK/Rac and Hippo/YAP-TAZ/TEAD, through direct binding but also interacts with Ras/MEK/ERK and mTOR signaling through mechanisms that are not well established.&nbsp; There are no FDA approved treatments for NF2, though several drugs, including brigatinib (Plotkin Scott et al., 2024) and bevacizumab (Plotkin et al., 2019), have been beneficial in small scale clinical trials.</p><p>&nbsp;</p><p>A new class of compounds that inhibit Hippo signaling by binding an auto-palmitoylation pocket in the YAP/TAZ partner, TEAD (Tang et al., 2021), shows some clinical efficacy in NF2-dependent mesotheliomas (Yap et al., 2025).&nbsp; There was also some efficacy in preclinical models of NF2-Schwannomas either alone or together with PAK inhibitors (Benton et al., 2024; Laraba et al., 2023).&nbsp; We performed unbiased cell-based combination screens with a TEAD inhibitor, hypothesizing that, like YAP/TAZ knockdowns, it will synergize with inhibitors of Ras signals, such as MEK and mTOR inhibitors (White et al., 2019).</p><p><b>&nbsp;</b></p><p>We used a high-throughput strategy (HTS) to screen 123 anti-neoplastic drugs against NF1 and NF2 cells, using a library with both classical chemotherapy and targeted therapeutics.&nbsp; The IC50s were determined from eight concentrations of drugs ranging from 4.6 nM to 10 mM.&nbsp; The cell lines screened were the NF1 MPNST line ST88-14, the mouse NF2 schwannoma cell line SC4 and the human NF2 Schwannoma cell line HEI193.&nbsp; Primary screening was done both with and without 2 mM of the TEAD1 selective inhibitor VT103 and summarized by a heatmap in Figure 1A (expanded in Figure 1B for clarity).&nbsp; VT103 was not active under these conditions, but it caused downward IC50 shifts for multiple compounds, suggesting it may potentiate their activity.&nbsp; To quantify hits and other candidate drugs, we next tested over 300 combinations of drugs and cells using 6×6 titrations in microtiter plates and then analyzed data with SynergyFinder (Zheng et al., 2022). &nbsp;In this algorithm, a zero interaction potency (ZIP) synergy score &gt;10 is highly synergistic.&nbsp; ZIP synergy scores &gt;10 in at least one cell line were observed for eight of the 10 hits, with only decitabine and JQ1 yielding low ZIP synergy scores. &nbsp;The highest ZIP scores (~65) in SC4 were for VT103 combinations with MEK inhibitors (trametinib and selumetinib), SHP2 inhibitors (TNO155 was substituted for SHP099) (Ahmari et al., 2025; Wang et al., 2020), and mTOR inhibitors (everolimus). &nbsp;ST88-14 and HEI193 exhibited positive but lower synergy magnitudes, maintaining almost the same rank order of top VT103 partners. &nbsp;Comparable synergy scores were seen using three other TEAD inhibitors with several of these combinations.&nbsp; Weaker synergies were detected for glutaminase inhibitors (BPTES, UPGL and 968) (Han et al., 2017) and the EZH2 inhibitor UNC1999.</p><p><b>&nbsp;</b></p><p>VT103 synergized most consistently with inhibitors targeting the RAS/MAPK signaling (MEK, SHP2) and mTOR signaling in both NF1 and NF2 cells.&nbsp; Data with PAK inhibitors suggest some synergy, but this was difficult to assess, as PAK inhibitors (Frax 486) are potent as single agents and strong single agents can reduce synergies in this assay (Benton et al., 2024; Guo et al., 2017). &nbsp;These findings suggest that VT103 deepens ERK pathway suppression.&nbsp; This may be because loss of YAP/TAZ activation causes an activation of ERK. &nbsp;Thus, inhibiting ERK is needed after Hippo inhibition.&nbsp; The strongest synergy was observed in the NF2 line SC4.&nbsp;</p><p>&nbsp;</p><p>The Hippo pathway effectors YAP/TAZ drive NF2 tumors as well as Ras driven tumors that become resistant to MEK inhibitors (Edwards et al., 2023; Kim et al., 2016; Lin et al., 2015; White et al., 2019).&nbsp; YAP and TAZ are partners for TEAD, which combine to make a functional transcription factor.&nbsp; While most studies, to date, tested the Hippo pathway using genetic strategies that inhibit YAP and TAZ, which cannot yet be inhibited with small molecules, it was not clear if inhibition at the level of TEAD is sufficient.&nbsp; Our data suggests TEAD inhibitors have partial effects as single agents, but they are strongly synergistic with Ras pathway inhibitors.&nbsp; Surprisingly, despite multiple TEAD isoforms, tests with multiple TEAD inhibitors suggest that inhibition of TEAD1 alone may be sufficient to inhibit NF1 and NF2 cells.&nbsp; The synergy with glutaminase and epigenetic inhibitors suggests metabolic and epigenetic pathways may also be exploitable with TEAD inhibitor combination strategies.&nbsp;</p><p>&nbsp;</p><p><b>Limitations of this study: </b>&nbsp;Cell screening studies can identify combinations as starting points for animal and perhaps clinical studies.&nbsp; However, only 5-10% of cell and animal studies translate to clinical benefit.&nbsp; For example, MEK and MTOR inhibitors, which are cytostatic in MPNST animal models, combine to shrink tumors, but showed little benefit in the clinic (Kim et al., 2026).</p><p>&nbsp;</p><p>&nbsp;</p><p><b>Methods</b></p><p>Cell lines (NF1: ST88-14; NF2: SC4, HEI193) were treated using a small molecule panel of inhibitors using a high-throughput format, as described, in the absence and presence of 2 µM VT103 (Guo et al., 2017).&nbsp; About 1000 cells per well were plated, and after ~24 hours, they were treated with drugs, incubated for ~72 hours and then tested for viability using ATPlite/luciferase analysis.&nbsp; The IC50 values were computed from dose–response curves, and compounds showing VT103-induced IC50 reductions were advanced into 6×6 dose-matrix combination assays. &nbsp;Drug concentrations for the matrices varied using 0x, 0.25x, 0.5x, 1x, 2x, and 4x of each drug, where x is the IC50 from panel A. &nbsp;Scoring used the ZIP reference model in SynergyFinder with default settings (Zheng et al., 2022).</p><p><b>&nbsp;</b></p><p>&nbsp;</p><p>&nbsp;</p><p><b>Acknowledgements</b>: We thank Dr. David Schultz from the High Throughput Screening Core of the Perelman School of Medicine for helpful discussions. &nbsp;We thank Tracy Tang and Len Post from Vivace Therapeutics for TEAD inhibitors.&nbsp; Supported by the AY GAPSA Provost Fellowship for Interdisciplinary Innovation, the Children’s Tumor Foundation (2019-05-004) and the DOD, (CDMRP NF180079).&nbsp;</p><p><b>&nbsp;</b></p><p><b>Data sharing.</b>&nbsp; Primary data from this manuscript is shared on Synapse and an interactive heat map showing dose response titrations of the drugs tested in Panel A are available on the Pharmacomb website ( <a href=\"https://www.med.upenn.edu/fieldlab/\">https://www.med.upenn.edu/fieldlab/</a> ).</p><p>&nbsp;</p><p>&nbsp;</p>","references":[{"reference":"<p>Ahmari N, Choi K, Wu J, Rizvi TA, Jackson M, Kershner LJ, et al., Ratner N. 2025. Daytime SHP2 inhibitor dosing, when immune cell numbers are elevated, shrinks neurofibromas. Life Sci Alliance 8(12): 10.26508/lsa.202503359.</p>","pubmedId":"40992926","doi":""},{"reference":"<p>Anastasaki C, Orozco P, Gutmann DH. 2022. RAS and beyond: the many faces of the neurofibromatosis type 1 protein. Dis Model Mech 15(2): 10.1242/dmm.049362.</p>","pubmedId":"35188187","doi":""},{"reference":"<p>Benton D, Yee Chow H, Karchugina S, Chernoff J. 2024. Synergistic effect of PAK and Hippo pathway inhibitor combination in NF2-deficient Schwannoma. PLoS One 19(7): e0305121.</p>","pubmedId":"39083549","doi":""},{"reference":"<p>de Blank PMK, Gross AM, Akshintala S, Blakeley JO, Bollag G, Cannon A, et al., Fisher MJ. 2022. MEK inhibitors for neurofibromatosis type 1 manifestations: Clinical evidence and consensus. Neuro Oncol 24(11): 1845-1856.</p>","pubmedId":"35788692","doi":""},{"reference":"<p>Edwards AC, Stalnecker CA, Jean Morales A, Taylor KE, Klomp JE, Klomp JA, et al., Der CJ. 2023. TEAD Inhibition Overcomes YAP1/TAZ-Driven Primary and Acquired Resistance to KRASG12C Inhibitors. Cancer Res 83(24): 4112-4129.</p>","pubmedId":"37934103","doi":""},{"reference":"<p>Gross AM, Wolters PL, Dombi E, Baldwin A, Whitcomb P, Fisher MJ, et al., Widemann BC. 2020. Selumetinib in Children with Inoperable Plexiform Neurofibromas. N Engl J Med 382(15): 1430-1442.</p>","pubmedId":"32187457","doi":""},{"reference":"<p>Guo J, Grovola MR, Xie H, Coggins GE, Duggan P, Hasan R, et al., Field J. 2017. Comprehensive pharmacological profiling of neurofibromatosis cell lines. Am J Cancer Res 7(4): 923-934.</p>","pubmedId":"28469964","doi":""},{"reference":"<p>Han T, Guo M, Zhang T, Gan M, Xie C, Wang JB. 2017. A novel glutaminase inhibitor-968 inhibits the migration and proliferation of non-small cell lung cancer cells by targeting EGFR/ERK signaling pathway. Oncotarget 8(17): 28063-28073.</p>","pubmedId":"28039459","doi":""},{"reference":"<p>Kim A, Ballman KV, Wolters PL, Heise RS, Shern JF, Sundby RT, et al., Widemann BC. 2026. SARC031: A Phase II Trial of Selumetinib and Sirolimus for Patients with Unresectable or Metastatic Malignant Peripheral Nerve Sheath Tumors (MPNST). Clin Cancer Res 32(6): 1068-1077.</p>","pubmedId":"41504652","doi":""},{"reference":"<p>Kim MH, Kim J, Hong H, Lee SH, Lee JK, Jung E, Kim J. 2016. Actin remodeling confers BRAF inhibitor resistance to melanoma cells through YAP/TAZ activation. EMBO J 35(5): 462-78.</p>","pubmedId":"26668268","doi":""},{"reference":"<p>Laraba L, Hillson L, de Guibert JG, Hewitt A, Jaques MR, Tang TT, et al., Parkinson DB. 2023. Inhibition of YAP/TAZ-driven TEAD activity prevents growth of NF2-null schwannoma and meningioma. Brain 146(4): 1697-1713.</p>","pubmedId":"36148553","doi":""},{"reference":"<p>Lin L, Sabnis AJ, Chan E, Olivas V, Cade L, Pazarentzos E, et al., Bivona TG. 2015. The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies. Nat Genet 47(3): 250-6.</p>","pubmedId":"25665005","doi":""},{"reference":"<p>Plotkin SR, Yohay KH, Nghiemphu PL, Dinh CT, Babovic-Vuksanovic D, Merker VL, et al., INTUITT-NF2 Consortium. 2024. Brigatinib in NF2-Related Schwannomatosis with Progressive Tumors. N Engl J Med 390(24): 2284-2294.</p>","pubmedId":"38904277","doi":""},{"reference":"<p>Plotkin SR, Duda DG, Muzikansky A, Allen J, Blakeley J, Rosser T, et al., Karajannis MA. 2019. Multicenter, Prospective, Phase II and Biomarker Study of High-Dose Bevacizumab as Induction Therapy in Patients With Neurofibromatosis Type 2 and Progressive Vestibular Schwannoma. J Clin Oncol 37(35): 3446-3454.</p>","pubmedId":"31626572","doi":""},{"reference":"<p>Tang TT, Konradi AW, Feng Y, Peng X, Ma M, Li J, et al., Post L. 2021. Small Molecule Inhibitors of TEAD Auto-palmitoylation Selectively Inhibit Proliferation and Tumor Growth of NF2-deficient Mesothelioma. Mol Cancer Ther 20(6): 986-998.</p>","pubmedId":"33850002","doi":""},{"reference":"<p>Wang J, Pollard K, Allen AN, Tomar T, Pijnenburg D, Yao Z, Rodriguez FJ, Pratilas CA. 2020. Combined Inhibition of SHP2 and MEK Is Effective in Models of NF1-Deficient Malignant Peripheral Nerve Sheath Tumors. Cancer Res 80(23): 5367-5379.</p>","pubmedId":"33032988","doi":""},{"reference":"<p>White SM, Avantaggiati ML, Nemazanyy I, Di Poto C, Yang Y, Pende M, et al., Yi C. 2019. YAP/TAZ Inhibition Induces Metabolic and Signaling Rewiring Resulting in Targetable Vulnerabilities in NF2-Deficient Tumor Cells. Dev Cell 49(3): 425-443.e9.</p>","pubmedId":"31063758","doi":""},{"reference":"<p>Yap TA, Kwiatkowski DJ, Dagogo-Jack I, Offin M, Zauderer MG, Kratzke R, et al., Kindler HL. 2025. YAP/TEAD inhibitor VT3989 in solid tumors: a phase 1/2 trial. Nat Med 31(12): 4281-4290.</p>","pubmedId":"41111090","doi":""},{"reference":"<p>Zheng S, Wang W, Aldahdooh J, Malyutina A, Shadbahr T, Tanoli Z, Pessia A, Tang J. 2022. SynergyFinder Plus: Toward Better Interpretation and Annotation of Drug Combination Screening Datasets. Genomics Proteomics Bioinformatics 20(3): 587-596.</p>","pubmedId":"35085776","doi":""}],"title":"<p>TEAD inhibitors synergize with MEK, SHP2 and mTOR inhibitors in NF1 and NF2 cell lines</p>","reviews":[{"reviewer":{"displayName":"Emilia  Galperin "},"openAcknowledgement":false,"status":{"submitted":true}}],"curatorReviews":[]},{"id":"1622b310-97d7-4055-b669-10f7e7627d1a","decision":"accept","abstract":"<p>Neurofibromatosis type 1 (NF1) and <i>NF2</i>-related Schwannomatosis (<i>NF2</i>-SWN) are both inherited tumor syndromes characterized by Schwann cell tumors.&nbsp; NF1 tumors harbor activated Ras/MEK/ERK, while <i>NF2</i>-SWN tumors harbor activated mechanosignaling pathways, including Hippo/YAP-TAZ/TEAD.&nbsp; To test combinatorial strategies in tumor cell lines, we first screened a new-generation TEAD inhibitor, VT103, against 123 drugs and then validated the hits with pairwise titrations.&nbsp; VT103 consistently synergized with inhibitors of MEK (MEK: trametinib and selumetinib; SHP2:&nbsp; TNO155) and mTOR (everolimus).&nbsp; The highest synergy (SynergyFinder ZIP~65) was in the <i>NF2</i>-SWN cell line SC4, with lower magnitudes in an NF1 cell line.</p>","acknowledgements":"<p>We thank Dr. David Schultz from the High Throughput Screening Core of the Perelman School of Medicine for helpful discussions, and the students of Chem 495 for assistance.&nbsp; We thank Drs. Nancy Ratner and Jonathan Chernoff for MPNST cells and Dr. Marco Giovannini for HEI-193 and SC4 cells.&nbsp; We thank Tracy Tang and Len Post from Vivace Therapeutics for TEAD inhibitors.&nbsp;</p>","authors":[{"affiliations":["University of Pennsylvania","Harvard University, Cambridge, MA, US"],"departments":["Systems Pharmacology and Translational Therapeutics",""],"credit":["investigation","dataCuration","formalAnalysis"],"email":"yyang60@mgh.harvard.edu","firstName":"Yang","lastName":"Yang","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":"ORC ID 0000-0003-3801-681X"},{"affiliations":["University of Pennsylvania, Philadelphia, PA, US"],"departments":["Systems Pharmacology and Translational Therapeutics"],"credit":["investigation","dataCuration","formalAnalysis"],"email":"sharavana.gurunathan@pennmedicine.upenn.edu","firstName":"Sharavana","lastName":"Gurunathan","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":"0000-0001-9817-7282"},{"affiliations":["University of Pennsylvania, Philadelphia, PA, US"],"departments":["Systems Pharmacology and Translational Therapeutics "],"credit":["dataCuration","writing_reviewEditing"],"email":"shsch@seas.upenn.edu","firstName":"Shane","lastName":"Schechter","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":"0009-0007-8411-8864"},{"affiliations":["University of Pennsylvania, Philadelphia, PA, US"],"departments":["Systems Pharmacology and Translational Therapeutics"],"credit":["conceptualization","fundingAcquisition","project","writing_originalDraft"],"email":"jfield@upenn.edu","firstName":"Jeffrey","lastName":"Field","submittingAuthor":true,"correspondingAuthor":true,"equalContribution":false,"WBId":null,"orcid":"0000-0001-7161-7284"}],"awards":[],"conflictsOfInterest":"<p>The authors declare that there are no conflicts of interest present.</p>","dataTable":{"url":null},"extendedData":[],"funding":"<p>Supported by the AY GAPSA Provost Fellowship for Interdisciplinary Innovation, the Children’s Tumor Foundation (2019-05-004) and the DOD, (CDMRP NF180079).</p>","image":{"url":"https://portal.micropublication.org/uploads/fe3426b08d2c1d5f907fc1752805836b.png"},"imageCaption":"<p>(A) Large-scale heatmap shows IC<sub>50</sub> values for a compound panel in NF1 and <i>NF2</i>-SWN lines ± 2 µM VT103.&nbsp; (B) Focused heatmap highlights agents with VT103-induced IC<sub>50</sub> reductions.&nbsp; (C) Bar plots ranking ZIP synergy scores from 6×6 matrices in ST88-14 (NF1), SC4 (<i>NF2</i>-SWN), and HEI193 (<i>NF2</i>-SWN), respectively.</p>","imageTitle":"<p>NF1 and <i>NF2</i>-SWN screening and synergy analyses</p>","methods":"<p></p>","reagents":"<p></p>","patternDescription":"<p><b>Description</b></p><p>Neurofibromatosis type 1 (NF1) and type 2 (NF2) are both autosomal dominant syndromes driven by loss-of-function mutations in <i>NF1</i> (neurofibromin) and <i>NF2</i> (Merlin), respectively.&nbsp; Patients harbor mutant copies of either <i>NF1</i>or <i>NF2</i>, usually from birth.&nbsp; A major aspect of the morbidity of both syndromes are multiple benign tumors.&nbsp; Tumors develop when sporadic mutations occur in the wild-type copy in Schwann cells.&nbsp; NF1 patients develop neurofibromas, a heterogeneous mixture of Schwann cells, mast cells and fibroblasts, while <i>NF2</i>-SWN patients develop Schwannomas, which primarily contain Schwann cells.&nbsp; About 10% of NF1 patients will develop malignant peripheral nerve sheath tumors (MPNST) from neurofibromas.&nbsp; NF1 and <i>NF2</i>-SWN cell comparisons are useful in drug screens because they are both derived from Schwann cells but have distinct primary driver mutations.</p><p>&nbsp;</p><p>Neurofibromin is a RasGAP, so NF1 loss results in constitutive activation of RAS and its downstream signals through Raf/MEK/ERK and PI3K/mTOR.&nbsp; Several MEK inhibitors are FDA approved to treat NF1 neurofibromas (Anastasaki et al., 2022).&nbsp; Though MPNST cell models respond to MEK inhibitors, MPNST patients show little response to MEK inhibitors as single agents or in combination with mTOR inhibitors (de Blank et al., 2022; Gross et al., 2020; Kim et al., 2026).&nbsp; More recently the Hippo pathway was identified as an additional driver of MPNST (Wu et al., 2018).</p><p>&nbsp;</p><p>Merlin is a cytoskeletal protein and its loss in <i>NF2</i>-SWN tumors activates several mechanosignaling pathways through direct binding, including PAK/Rac and Hippo/YAP-TAZ/TEAD, but also interacts indirectly with Ras/MEK/ERK and mTOR signaling through mechanisms that are not well established.&nbsp; There are no FDA approved treatments for<i> NF2</i>-SWN, though several drugs, including brigatinib (Plotkin Scott et al., 2024) and bevacizumab (Plotkin et al., 2019), have been beneficial in small scale clinical trials (Evans, 1993).</p><p>&nbsp;</p><p>The dependence of both tumors on Ras, mTOR and Hippo signaling suggests that combinations of drugs targeting these pathways may be beneficial for both NF1 and <i>NF2</i>-SWN tumors.&nbsp; It has been difficult to develop drugs against Hippo but a new class of compounds that inhibit Hippo signaling by binding an auto-palmitoylation pocket in the YAP/TAZ partner, TEAD (Tang et al., 2021), shows some clinical efficacy in <i>NF2</i>-dependent mesotheliomas (Yap et al., 2025).&nbsp; There was also some efficacy in preclinical models of <i>NF2</i>-SWN either alone or together with PAK inhibitors (Benton et al., 2024; Laraba et al., 2023).&nbsp; We performed unbiased cell-based combination screens with a TEAD inhibitor, hypothesizing that, like YAP/TAZ knockdowns, it will synergize with inhibitors of Ras signals, such as MEK and mTOR inhibitors (White et al., 2019).</p><p><b>&nbsp;</b></p><p>High-throughput screening (HTS) of drugs against cancer cell lines has been effective as a first step to prioritize drugs for animal clinical testing.&nbsp; The pioneering large-scale screening of a panel of 60 cell lines, the NCI-60, established that the most effective comparisons were between different cancer types, including those with different driver mutations (Shoemaker, 2006).&nbsp; HTS of drug pairs also helps prioritize drug combinations to test (Holbeck et al., 2017). &nbsp;We used a HTS strategy to screen NF1 and <i>NF2</i>-SWN cells.&nbsp; There are only a few NF1 and NF2 cell lines because they are rare tumors.&nbsp; The cell lines screened were the NF1 MPNST line ST88-14, the mouse <i>NF2</i>-SWN cell line SC4 and the human <i>NF2</i>-SWN Schwannoma cell line HEI193, which have been extensively characterized (Guo et al., 2017; Hung et al., 2002; Magallón-Lorenz et al., 2023; Teicher et al., 2015; Yang et al., 2011).&nbsp;</p><p>&nbsp;</p><p>We screened 123 anti-neoplastic drugs using a library comprised of both classical chemotherapy and targeted therapeutics.&nbsp; The IC<sub>50</sub> values were determined from eight concentrations of drugs ranging from 4.6 nM to 10 mM.&nbsp; Primary screening was done both with and without 2 mM of the TEAD1 selective inhibitor VT103 and summarized by a heatmap in Figure 1A (expanded in Figure 1B for clarity).&nbsp; VT103 was not active under these conditions, but it caused downward IC<sub>50</sub> shifts for multiple compounds, suggesting it may potentiate their activity.&nbsp; To quantify hits and other candidate drugs, we next tested over 300 combinations of drugs and cells using 6×6 titrations in microtiter plates and then analyzed data with SynergyFinder (Zheng et al., 2022). &nbsp;In this algorithm, a zero-interaction potency (ZIP) synergy score &gt;10 is highly synergistic.&nbsp; ZIP synergy scores &gt;10 in at least one cell line were observed for eight of the 10 hits, with only decitabine and JQ1 yielding low ZIP synergy scores. &nbsp;The highest ZIP scores (~65) in SC4 were for VT103 combinations with MEK inhibitors (trametinib and selumetinib), SHP2 inhibitors (TNO155 was substituted for SHP099) (Ahmari et al., 2025; Wang et al., 2020), and mTOR inhibitors (everolimus). &nbsp;ST88-14 and HEI193 exhibited positive but lower synergy magnitudes, maintaining almost the same rank order of top VT103 partners. &nbsp;Comparable synergy scores were seen using three other TEAD inhibitors with several of these combinations.&nbsp; Weaker synergies were detected for glutaminase inhibitors (BPTES, UPGL, and 968) (Han et al., 2017) and the EZH2 inhibitor UNC1999.</p><p><b>&nbsp;</b></p><p>VT103 synergized most consistently with inhibitors targeting the RAS/MAPK signaling (MEK, SHP2) and mTOR signaling in both NF1 and <i>NF2</i>-SWN cells.&nbsp; Data with PAK inhibitors suggest some synergy, but this was difficult to assess, as PAK inhibitors (Frax 486) are potent as single agents and strong single agents can reduce synergies in this assay (Benton et al., 2024; Guo et al., 2017). &nbsp;These findings suggest that VT103 deepens ERK pathway suppression.&nbsp; This may be because loss of YAP/TAZ activation causes an activation of ERK. &nbsp;Thus, inhibiting ERK is needed after Hippo inhibition.&nbsp; The strongest synergy was observed in the <i>NF2</i>-SWN line SC4.&nbsp;</p><p>&nbsp;</p><p>The Hippo pathway effectors YAP/TAZ drive <i>NF2</i>-SWN tumors as well as Ras driven tumors that become resistant to MEK inhibitors (Edwards et al., 2023; Kim et al., 2016; Lin et al., 2015; White et al., 2019).&nbsp; YAP and TAZ are partners for TEAD, which combine to make a functional transcription factor.&nbsp; While most studies, to date, tested the Hippo pathway using genetic methods to inhibit YAP and TAZ, which cannot yet be inhibited with small molecules, it was not clear if inhibition at the level of TEAD is sufficient.&nbsp; Our data suggests TEAD inhibitors have partial effects as single agents, but they are strongly synergistic with Ras pathway inhibitors.&nbsp; Surprisingly, despite multiple TEAD isoforms, tests with multiple TEAD inhibitors suggest that inhibition of TEAD1 alone may be sufficient to inhibit <i>NF1</i>and <i>NF2</i>-SWN cells.&nbsp; The synergy with glutaminase and epigenetic inhibitors suggests metabolic and epigenetic pathways may also be exploitable with TEAD inhibitor combination strategies.&nbsp;</p><p>&nbsp;</p><p><b>Limitations of this study: </b>&nbsp;Cell screening studies can identify combinations as starting points for animal and perhaps clinical studies.&nbsp; However, only 5-10% of cell and animal studies translate to clinical benefit.&nbsp; For example, MEK and MTOR inhibitors (Kahen et al., 2018), which are cytostatic in MPNST animal models, shrink tumors in combination, but were of little benefit in a clinical trial (Kim et al., 2026).</p><p>&nbsp;</p><p>&nbsp;</p><p><b>Methods</b></p><p>ST88-14 identity was confirmed by STR profiling.&nbsp; Cell lines were grown and treated using a small molecule panel of inhibitors using a high-throughput format, as described, in the absence and presence of 2 µM VT103 (Guo et al., 2017).&nbsp; About 1000 cells per well were plated, and after ~24 hours, they were treated with drugs, incubated for ~72 hours and then tested for viability using ATPlite/luciferase analysis.&nbsp; The IC<sub>50</sub> values were computed from dose–response curves, and compounds showing VT103-induced IC<sub>50</sub> reductions were advanced into 6×6 dose-matrix combination assays. &nbsp;Drug concentrations for the matrices varied using 0x, 0.25x, 0.5x, 1x, 2x, and 4x of each drug, where x is the IC<sub>50</sub>from panel A. &nbsp;Scoring used the ZIP reference model in SynergyFinder with default settings (Zheng et al., 2022).</p><p><b>&nbsp;</b></p><p><b>Data sharing.</b>&nbsp; Primary data from this manuscript is shared on Synapse and an interactive heat map showing dose response titrations of the drugs tested in Panel A are available on the Pharmacomb website ( <a href=\"https://www.med.upenn.edu/fieldlab/\">https://www.med.upenn.edu/fieldlab/</a> ).</p><p>&nbsp;</p><p>&nbsp;</p><p>&nbsp;</p>","references":[{"reference":"<p>Ahmari N, Choi K, Wu J, Rizvi TA, Jackson M, Kershner LJ, et al., Ratner N. 2025. Daytime SHP2 inhibitor dosing, when immune cell numbers are elevated, shrinks neurofibromas. Life Sci Alliance 8(12): 10.26508/lsa.202503359.</p>","pubmedId":"40992926","doi":""},{"reference":"<p>Anastasaki C, Orozco P, Gutmann DH. 2022. RAS and beyond: the many faces of the neurofibromatosis type 1 protein. Dis Model Mech 15(2): 10.1242/dmm.049362.</p>","pubmedId":"35188187","doi":""},{"reference":"<p>Benton D, Yee Chow H, Karchugina S, Chernoff J. 2024. Synergistic effect of PAK and Hippo pathway inhibitor combination in NF2-deficient Schwannoma. PLoS One 19(7): e0305121.</p>","pubmedId":"39083549","doi":""},{"reference":"<p>de Blank PMK, Gross AM, Akshintala S, Blakeley JO, Bollag G, Cannon A, et al., Fisher MJ. 2022. MEK inhibitors for neurofibromatosis type 1 manifestations: Clinical evidence and consensus. Neuro Oncol 24(11): 1845-1856.</p>","pubmedId":"35788692","doi":""},{"reference":"<p>Edwards AC, Stalnecker CA, Jean Morales A, Taylor KE, Klomp JE, Klomp JA, et al., Der CJ. 2023. TEAD Inhibition Overcomes YAP1/TAZ-Driven Primary and Acquired Resistance to KRASG12C Inhibitors. Cancer Res 83(24): 4112-4129.</p>","pubmedId":"37934103","doi":""},{"reference":"<p>Evans DG, Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, 1993. NF2-Related Schwannomatosis. University of Washington, Seattle.</p>","pubmedId":"20301380","doi":""},{"reference":"<p>Gross AM, Wolters PL, Dombi E, Baldwin A, Whitcomb P, Fisher MJ, et al., Widemann BC. 2020. Selumetinib in Children with Inoperable Plexiform Neurofibromas. N Engl J Med 382(15): 1430-1442.</p>","pubmedId":"32187457","doi":""},{"reference":"<p>Guo J, Grovola MR, Xie H, Coggins GE, Duggan P, Hasan R, et al., Field J. 2017. Comprehensive pharmacological profiling of neurofibromatosis cell lines. Am J Cancer Res 7(4): 923-934.</p>","pubmedId":"28469964","doi":""},{"reference":"<p>Han T, Guo M, Zhang T, Gan M, Xie C, Wang JB. 2017. A novel glutaminase inhibitor-968 inhibits the migration and proliferation of non-small cell lung cancer cells by targeting EGFR/ERK signaling pathway. Oncotarget 8(17): 28063-28073.</p>","pubmedId":"28039459","doi":""},{"reference":"<p>Holbeck SL, Camalier R, Crowell JA, Govindharajulu JP, Hollingshead M, Anderson LW, et al., Doroshow JH. 2017. The National Cancer Institute ALMANAC: A Comprehensive Screening Resource for the Detection of Anticancer Drug Pairs with Enhanced Therapeutic Activity. Cancer Res 77(13): 3564-3576.</p>","pubmedId":"28446463","doi":""},{"reference":"<p>Hung G, Li X, Faudoa R, Xeu Z, Kluwe L, Rhim JS, Slattery W, Lim D. 2002. Establishment and characterization of a schwannoma cell line from a patient with neurofibromatosis 2. Int J Oncol 20(3): 475-82.</p>","pubmedId":"11836557","doi":""},{"reference":"<p>Kahen EJ, Brohl A, Yu D, Welch D, Cubitt CL, Lee JK, et al., Reed DR. 2018. Neurofibromin level directs RAS pathway signaling and mediates sensitivity to targeted agents in malignant peripheral nerve sheath tumors. Oncotarget 9(32): 22571-22585.</p>","pubmedId":"29854299","doi":""},{"reference":"<p>Kim A, Ballman KV, Wolters PL, Heise RS, Shern JF, Sundby RT, et al., Widemann BC. 2026. SARC031: A Phase II Trial of Selumetinib and Sirolimus for Patients with Unresectable or Metastatic Malignant Peripheral Nerve Sheath Tumors (MPNST). Clin Cancer Res 32(6): 1068-1077.</p>","pubmedId":"41504652","doi":""},{"reference":"<p>Kim MH, Kim J, Hong H, Lee SH, Lee JK, Jung E, Kim J. 2016. Actin remodeling confers BRAF inhibitor resistance to melanoma cells through YAP/TAZ activation. EMBO J 35(5): 462-78.</p>","pubmedId":"26668268","doi":""},{"reference":"<p>Laraba L, Hillson L, de Guibert JG, Hewitt A, Jaques MR, Tang TT, et al., Parkinson DB. 2023. Inhibition of YAP/TAZ-driven TEAD activity prevents growth of NF2-null schwannoma and meningioma. Brain 146(4): 1697-1713.</p>","pubmedId":"36148553","doi":""},{"reference":"<p>Lin L, Sabnis AJ, Chan E, Olivas V, Cade L, Pazarentzos E, et al., Bivona TG. 2015. The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies. Nat Genet 47(3): 250-6.</p>","pubmedId":"25665005","doi":""},{"reference":"<p>Magallón-Lorenz M, Terribas E, Ortega-Bertran S, Creus-Bachiller E, Fernández M, Requena G, et al., Serra E. 2023. Deep genomic analysis of malignant peripheral nerve sheath tumor cell lines challenges current malignant peripheral nerve sheath tumor diagnosis. iScience 26(2): 106096.</p>","pubmedId":"36818284","doi":""},{"reference":"<p>Plotkin SR, Duda DG, Muzikansky A, Allen J, Blakeley J, Rosser T, et al., Karajannis MA. 2019. Multicenter, Prospective, Phase II and Biomarker Study of High-Dose Bevacizumab as Induction Therapy in Patients With Neurofibromatosis Type 2 and Progressive Vestibular Schwannoma. J Clin Oncol 37(35): 3446-3454.</p>","pubmedId":"31626572","doi":""},{"reference":"<p>Plotkin SR, Yohay KH, Nghiemphu PL, Dinh CT, Babovic-Vuksanovic D, Merker VL, et al., INTUITT-NF2 Consortium. 2024. Brigatinib in NF2-Related Schwannomatosis with Progressive Tumors. N Engl J Med 390(24): 2284-2294.</p>","pubmedId":"38904277","doi":""},{"reference":"<p>Shoemaker RH. 2006. The NCI60 human tumour cell line anticancer drug screen. Nat Rev Cancer 6(10): 813-23.</p>","pubmedId":"16990858","doi":""},{"reference":"<p>Tang TT, Konradi AW, Feng Y, Peng X, Ma M, Li J, et al., Post L. 2021. Small Molecule Inhibitors of TEAD Auto-palmitoylation Selectively Inhibit Proliferation and Tumor Growth of NF2-deficient Mesothelioma. Mol Cancer Ther 20(6): 986-998.</p>","pubmedId":"33850002","doi":""},{"reference":"<p>Teicher BA, Polley E, Kunkel M, Evans D, Silvers T, Delosh R, et al., Morris J. 2015. Sarcoma Cell Line Screen of Oncology Drugs and Investigational Agents Identifies Patterns Associated with Gene and microRNA Expression. Mol Cancer Ther 14(11): 2452-62.</p>","pubmedId":"26351324","doi":""},{"reference":"<p>Wang J, Pollard K, Allen AN, Tomar T, Pijnenburg D, Yao Z, Rodriguez FJ, Pratilas CA. 2020. Combined Inhibition of SHP2 and MEK Is Effective in Models of NF1-Deficient Malignant Peripheral Nerve Sheath Tumors. Cancer Res 80(23): 5367-5379.</p>","pubmedId":"33032988","doi":""},{"reference":"<p>White SM, Avantaggiati ML, Nemazanyy I, Di Poto C, Yang Y, Pende M, et al., Yi C. 2019. YAP/TAZ Inhibition Induces Metabolic and Signaling Rewiring Resulting in Targetable Vulnerabilities in NF2-Deficient Tumor Cells. Dev Cell 49(3): 425-443.e9.</p>","pubmedId":"31063758","doi":""},{"reference":"<p>Wu LMN, Deng Y, Wang J, Zhao C, Wang J, Rao R, et al., Lu QR. 2018. Programming of Schwann Cells by Lats1/2-TAZ/YAP Signaling Drives Malignant Peripheral Nerve Sheath Tumorigenesis. Cancer Cell 33(2): 292-308.e7.</p>","pubmedId":"29438698","doi":""},{"reference":"<p>Yang J, Ylipää A, Sun Y, Zheng H, Chen K, Nykter M, et al., Zhang W. 2011. Genomic and molecular characterization of malignant peripheral nerve sheath tumor identifies the IGF1R pathway as a primary target for treatment. Clin Cancer Res 17(24): 7563-73.</p>","pubmedId":"22042973","doi":""},{"reference":"<p>Yap TA, Kwiatkowski DJ, Dagogo-Jack I, Offin M, Zauderer MG, Kratzke R, et al., Kindler HL. 2025. YAP/TEAD inhibitor VT3989 in solid tumors: a phase 1/2 trial. Nat Med 31(12): 4281-4290.</p>","pubmedId":"41111090","doi":""},{"reference":"<p>Zheng S, Wang W, Aldahdooh J, Malyutina A, Shadbahr T, Tanoli Z, Pessia A, Tang J. 2022. SynergyFinder Plus: Toward Better Interpretation and Annotation of Drug Combination Screening Datasets. Genomics Proteomics Bioinformatics 20(3): 587-596.</p>","pubmedId":"35085776","doi":""}],"title":"<p>TEAD inhibitors synergize with MEK, SHP2 and mTOR inhibitors in NF1 and NF2 cell lines</p>","reviews":[],"curatorReviews":[]},{"id":"b11cb1f9-bcb3-4c7d-913f-ec07a9227160","decision":"publish","abstract":"<p>Neurofibromatosis type 1 (NF1) and <i>NF2</i>-related Schwannomatosis (<i>NF2</i>-SWN) are both inherited syndromes characterized by Schwann cell tumors.&nbsp; NF1 tumors harbor activated Ras/MEK/ERK, while <i>NF2</i>-SWN tumors harbor activated mechanosignaling pathways, including Hippo/YAP-TAZ/TEAD.&nbsp; To test combinatorial strategies in tumor cell lines, we first screened a new-generation TEAD inhibitor, VT103, against 123 drugs and then validated the hits with pairwise titrations.&nbsp; VT103 consistently synergized with inhibitors of MEK (trametinib and selumetinib), SHP2 (TNO155) and mTOR (everolimus).&nbsp; The highest synergy ZIP score, calculated using SynergyFinder, was ~65 in the <i>NF2</i>-SWN cell line SC4, with lower magnitudes in an NF1 cell line.</p>","acknowledgements":"<p>We thank Dr. David Schultz from the High Throughput Screening Core of the Perelman School of Medicine for helpful discussions, and the students of CHEM 495 for assistance.&nbsp; We thank Drs. Nancy Ratner and Jonathan Chernoff for MPNST cells and Dr. Marco Giovannini for HEI-193 and SC4 cells.&nbsp; We thank Tracy Tang and Len Post from Vivace Therapeutics for the TEAD inhibitors.&nbsp;</p>","authors":[{"affiliations":["University of Pennsylvania","Harvard University, Cambridge, MA, US"],"departments":["Systems Pharmacology and Translational Therapeutics",""],"credit":["investigation","dataCuration","formalAnalysis"],"email":"yyang60@mgh.harvard.edu","firstName":"Yang","lastName":"Yang","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":"ORC ID 0000-0003-3801-681X"},{"affiliations":["University of Pennsylvania, Philadelphia, PA, US"],"departments":["Systems Pharmacology and Translational Therapeutics"],"credit":["investigation","dataCuration","formalAnalysis"],"email":"sharavana.gurunathan@pennmedicine.upenn.edu","firstName":"Sharavana","lastName":"Gurunathan","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":"0000-0001-9817-7282"},{"affiliations":["University of Pennsylvania, Philadelphia, PA, US"],"departments":["Systems Pharmacology and Translational Therapeutics "],"credit":["dataCuration","writing_reviewEditing"],"email":"shsch@seas.upenn.edu","firstName":"Shane","lastName":"Schechter","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":"0009-0007-8411-8864"},{"affiliations":["University of Pennsylvania, Philadelphia, PA, US"],"departments":["Systems Pharmacology and Translational Therapeutics"],"credit":["conceptualization","fundingAcquisition","project","writing_originalDraft"],"email":"jfield@upenn.edu","firstName":"Jeffrey","lastName":"Field","submittingAuthor":true,"correspondingAuthor":true,"equalContribution":false,"WBId":null,"orcid":"0000-0001-7161-7284"}],"awards":[],"conflictsOfInterest":"<p>The authors declare that there are no conflicts of interest present.</p>","dataTable":{"url":null},"extendedData":[],"funding":"<p>Supported by the AY GAPSA Provost Fellowship for Interdisciplinary Innovation, the Children’s Tumor Foundation (2019-05-004) and the DOD (CDMRP NF180079).</p>","image":{"url":"https://portal.micropublication.org/uploads/fe3426b08d2c1d5f907fc1752805836b.png"},"imageCaption":"<p>(A) Large-scale heatmap shows IC<sub>50</sub> values for a compound panel in NF1 and <i>NF2</i>-SWN lines ± 2 µM VT103.&nbsp; (B) Focused heatmap highlights agents with VT103-induced IC<sub>50</sub> reductions.&nbsp; (C) Bar plots ranking ZIP synergy scores from 6×6 matrices in ST88-14 (NF1), SC4 (<i>NF2</i>-SWN), and HEI193 (<i>NF2</i>-SWN), respectively.</p>","imageTitle":"<p>NF1 and <i>NF2</i>-SWN screening and synergy analyses</p>","methods":"<p>ST88-14 identity was confirmed by STR profiling.&nbsp; Cell lines were grown and treated using a small molecule panel of inhibitors using a high-throughput format, as described, in the absence and presence of 2 µM VT103 (Guo et al., 2017).&nbsp; About 1000 cells per well were plated, and after ~24 hours, they were treated with drugs, incubated for ~72 hours and then tested for viability using ATPlite/luciferase analysis.&nbsp; The IC<sub>50</sub> values were computed from dose–response curves, and compounds showing VT103-induced IC<sub>50</sub> reductions were advanced into 6×6 dose-matrix combination assays. &nbsp;Drug concentrations for the matrices varied using 0x, 0.25x, 0.5x, 1x, 2x, and 4x of each drug, where x is the IC<sub>50</sub>from panel A. &nbsp;Scoring used the ZIP reference model in SynergyFinder with default settings (Zheng et al., 2022).</p><p><b>&nbsp;</b></p><p><b>Data sharing.</b>&nbsp; Primary data from this manuscript are shared on Synapse, and an interactive heat map showing dose-response titrations of the drugs tested in Panel A is available on the Pharmacomb website (<a href=\"https://www.med.upenn.edu/fieldlab/\">https://www.med.upenn.edu/fieldlab/</a>).</p>","reagents":"<p></p>","patternDescription":"<p>Neurofibromatosis type 1 (NF1) and type 2 (NF2) are both autosomal dominant syndromes driven by loss-of-function mutations in <i>NF1</i> (neurofibromin) and <i>NF2</i> (Merlin), respectively.&nbsp; Patients harbor mutant copies of either <i>NF1 </i>or <i>NF2</i>, usually from birth.&nbsp; A major aspect of the morbidity of both syndromes is multiple benign tumors, which develop when sporadic mutations occur in the wild-type copy in Schwann cells.&nbsp; NF1 patients develop neurofibromas, a heterogeneous mixture of Schwann cells, mast cells and fibroblasts, while <i>NF2</i>-SWN patients develop Schwannomas, which primarily contain Schwann cells.&nbsp; About 10% of NF1 patients will develop malignant peripheral nerve sheath tumors (MPNST) from neurofibromas.&nbsp; NF1 and <i>NF2</i>-SWN cell comparisons are useful in drug screens because they are both derived from Schwann cells but have distinct primary driver mutations.</p><p></p><p>Neurofibromin is a RasGAP, so NF1 loss results in constitutive activation of RAS and its downstream signals through Raf/MEK/ERK and PI3K/mTOR.&nbsp; Several MEK inhibitors are FDA-approved to treat NF1 neurofibromas (Anastasaki et al., 2022).&nbsp; Though MPNST cell models respond to MEK inhibitors, MPNST patients show little response to MEK inhibitors as single agents or in combination with mTOR inhibitors (de Blank et al., 2022; Gross et al., 2020; Kim et al., 2026).&nbsp; More recently, the Hippo pathway was identified as an additional driver of MPNST (Wu et al., 2018).</p><p>&nbsp;</p><p>Merlin is a cytoskeletal protein, and its loss in <i>NF2</i>-SWN tumors activates several mechanosignaling pathways through direct binding, including PAK/Rac and Hippo/YAP-TAZ/TEAD, but also interacts indirectly with Ras/MEK/ERK and mTOR signaling through mechanisms that are not well established.&nbsp; There are no FDA-approved treatments for<i>&nbsp;NF2</i>-SWN, though several drugs, including brigatinib (Plotkin Scott et al., 2024) and bevacizumab (Plotkin et al., 2019), have been beneficial in small-scale clinical trials (Evans, 1993).</p><p>&nbsp;</p><p>The dependence of both tumors on Ras, mTOR and Hippo signaling suggests that combinations of drugs targeting these pathways may be beneficial for both NF1 and <i>NF2</i>-SWN tumors.&nbsp; It has been difficult to develop drugs against Hippo, but a new class of compounds that inhibit Hippo signaling by binding an auto-palmitoylation pocket in the YAP/TAZ partner, TEAD (Tang et al., 2021), shows some clinical efficacy in <i>NF2</i>-dependent mesotheliomas (Yap et al., 2025).&nbsp; There was also some efficacy in preclinical models of <i>NF2</i>-SWN either alone or together with PAK inhibitors (Benton et al., 2024; Laraba et al., 2023).&nbsp; We performed unbiased cell-based combination screens with a TEAD inhibitor, hypothesizing that, like YAP/TAZ knockdowns, it would synergize with inhibitors of Ras signals, such as MEK and mTOR inhibitors (White et al., 2019).</p><p><b>&nbsp;</b></p><p>High-throughput screening (HTS) of drugs against cancer cell lines has been effective as a first step to prioritize drugs for animal clinical testing.&nbsp; The pioneering large-scale screening of a panel of 60 cell lines, the NCI-60, established that the most effective comparisons were between different cancer types, including those with different driver mutations (Shoemaker, 2006).&nbsp; HTS of drug pairs also helps prioritize drug combinations to test (Holbeck et al., 2017). &nbsp;We used a HTS strategy to screen NF1 and <i>NF2</i>-SWN cells.&nbsp; There are only a few NF1 and NF2 cell lines because they are rare tumors.&nbsp; The cell lines screened were the NF1 MPNST line ST88-14, the mouse <i>NF2</i>-SWN cell line SC4 and the human <i>NF2</i>-SWN Schwannoma cell line HEI193, which have been extensively characterized (Guo et al., 2017; Hung et al., 2002; Magallón-Lorenz et al., 2023; Teicher et al., 2015; Yang et al., 2011).&nbsp;</p><p>&nbsp;</p><p>We screened 123 anti-neoplastic drugs using a library comprised of both classical chemotherapy and targeted therapeutics.&nbsp; The IC<sub>50</sub> values were determined from eight concentrations of drugs ranging from 4.6 nM to 10 mM.&nbsp; Primary screening was done both with and without 2 mM of the TEAD1 selective inhibitor VT103 and summarized by a heatmap in Figure 1A (expanded in Figure 1B for clarity).&nbsp; VT103 was not active under these conditions, but it caused downward IC<sub>50</sub> shifts for multiple compounds, suggesting it may potentiate their activity.&nbsp; To quantify hits and other candidate drugs, we next tested over 300 combinations of drugs and cells using 6×6 titrations in microtiter plates and then analyzed data with SynergyFinder (Zheng et al., 2022). &nbsp;In this algorithm, a zero-interaction potency (ZIP) synergy score &gt;10 is highly synergistic.&nbsp; ZIP synergy scores &gt;10 in at least one cell line were observed for eight of the 10 hits, with only decitabine and JQ1 yielding low ZIP synergy scores. &nbsp;The highest ZIP scores (~65) in SC4 were for VT103 combinations with MEK inhibitors (trametinib and selumetinib), SHP2 inhibitors (TNO155 was substituted for SHP099) (Ahmari et al., 2025; Wang et al., 2020), and mTOR inhibitors (everolimus). &nbsp;ST88-14 and HEI193 exhibited positive but lower synergy magnitudes, maintaining almost the same rank order of top VT103 partners. &nbsp;Comparable synergy scores were seen using three other TEAD inhibitors with several of these combinations.&nbsp; Weaker synergies were detected for glutaminase inhibitors (BPTES, UPGL, and 968) (Han et al., 2017) and the EZH2 inhibitor UNC1999.</p><p><b>&nbsp;</b></p><p>VT103 synergized most consistently with inhibitors targeting the RAS/MAPK signaling (MEK, SHP2) and mTOR signaling in both NF1 and <i>NF2</i>-SWN cells.&nbsp; Data with PAK inhibitors suggest some synergy, but this was difficult to assess, as PAK inhibitors (Frax 486) are potent as single agents and strong single agents can reduce synergies in this assay (Benton et al., 2024; Guo et al., 2017). &nbsp;These findings suggest that VT103 deepens ERK pathway suppression.&nbsp; This may be because loss of YAP/TAZ activation causes an activation of ERK. &nbsp;Thus, inhibiting ERK is needed after Hippo inhibition.&nbsp; The strongest synergy was observed in the <i>NF2</i>-SWN line SC4.&nbsp;</p><p>&nbsp;</p><p>The Hippo pathway effectors YAP/TAZ drive <i>NF2</i>-SWN tumors as well as Ras-driven tumors that become resistant to MEK inhibitors (Edwards et al., 2023; Kim et al., 2016; Lin et al., 2015; White et al., 2019).&nbsp; YAP and TAZ are partners for TEAD, which combine to make a functional transcription factor.&nbsp; While most studies to date have tested the Hippo pathway using genetic methods to inhibit YAP and TAZ, which cannot yet be inhibited with small molecules, it remains unclear whether inhibition at the level of TEAD is sufficient.&nbsp; Our data suggest TEAD inhibitors have partial effects as single agents, but they are strongly synergistic with Ras pathway inhibitors.&nbsp; Surprisingly, despite multiple TEAD isoforms, tests with multiple TEAD inhibitors suggest that inhibition of TEAD1 alone may be sufficient to inhibit <i>NF1</i>and <i>NF2</i>-SWN cells.&nbsp; The synergy with glutaminase and epigenetic inhibitors suggests metabolic and epigenetic pathways may also be exploitable with TEAD inhibitor combination strategies.&nbsp;</p><p>&nbsp;</p><p><b>Limitations of this study: </b>&nbsp;Cell screening studies can identify combinations as starting points for animal and perhaps clinical studies.&nbsp; However, only 5-10% of cell and animal studies translate to clinical benefit.&nbsp; For example, MEK and MTOR inhibitors (Kahen et al., 2018), which are cytostatic in MPNST animal models, shrink tumors in combination, but were of little benefit in a clinical trial (Kim et al., 2026).&nbsp;&nbsp;</p>","references":[{"reference":"<p>Ahmari N, Choi K, Wu J, Rizvi TA, Jackson M, Kershner LJ, et al., Ratner N. 2025. Daytime SHP2 inhibitor dosing, when immune cell numbers are elevated, shrinks neurofibromas. Life Sci Alliance 8(12): 10.26508/lsa.202503359.</p>","pubmedId":"40992926","doi":""},{"reference":"<p>Anastasaki C, Orozco P, Gutmann DH. 2022. RAS and beyond: the many faces of the neurofibromatosis type 1 protein. Dis Model Mech 15(2): 10.1242/dmm.049362.</p>","pubmedId":"35188187","doi":""},{"reference":"<p>Benton D, Yee Chow H, Karchugina S, Chernoff J. 2024. Synergistic effect of PAK and Hippo pathway inhibitor combination in NF2-deficient Schwannoma. PLoS One 19(7): e0305121.</p>","pubmedId":"39083549","doi":""},{"reference":"<p>de Blank PMK, Gross AM, Akshintala S, Blakeley JO, Bollag G, Cannon A, et al., Fisher MJ. 2022. MEK inhibitors for neurofibromatosis type 1 manifestations: Clinical evidence and consensus. Neuro Oncol 24(11): 1845-1856.</p>","pubmedId":"35788692","doi":""},{"reference":"<p>Edwards AC, Stalnecker CA, Jean Morales A, Taylor KE, Klomp JE, Klomp JA, et al., Der CJ. 2023. TEAD Inhibition Overcomes YAP1/TAZ-Driven Primary and Acquired Resistance to KRASG12C Inhibitors. Cancer Res 83(24): 4112-4129.</p>","pubmedId":"37934103","doi":""},{"reference":"<p>Evans DG, Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, 1993. NF2-Related Schwannomatosis. University of Washington, Seattle.</p>","pubmedId":"20301380","doi":""},{"reference":"<p>Gross AM, Wolters PL, Dombi E, Baldwin A, Whitcomb P, Fisher MJ, et al., Widemann BC. 2020. Selumetinib in Children with Inoperable Plexiform Neurofibromas. N Engl J Med 382(15): 1430-1442.</p>","pubmedId":"32187457","doi":""},{"reference":"<p>Guo J, Grovola MR, Xie H, Coggins GE, Duggan P, Hasan R, et al., Field J. 2017. Comprehensive pharmacological profiling of neurofibromatosis cell lines. 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