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ResearchIn-Press PreviewCell biologyOncology Open Access | 10.1172/JCI201331

Combined FAK and MEK inhibition suppresses chromosome 8 gain malignant peripheral nerve sheath tumors

Guangfeng Wang,1 Dana C. Borcherding,1 Jiawan Wang,2 Xiaochun Zhang,1 Liuzhan Yang,1 Gorkem Oztosun,1 James J. Sears,1 Kangwen Xiao,1 Belinda B. Garana,3 Mark I. Zoberi,1 Aaron U. Bektas,1 Jeffrey J. Szymanski,4 Richa Rathore,5 Silvia Coma,5 Jonathan A. Pachter,5 Sara J.C. Gosline,3 Christine A. Pratilas,2 and Angela C. Hirbe1

1Department of Medicine, Division of Oncology, Washington University School of Medicine, Siteman Cancer Center, St. Louis, United States of America

2Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

3Division of Biological Sciences, Pacific Northwest National Laboratory, Seattle, United States of America

4Department of Radiation Oncology, Mayo Clinic, Rochester, United States of America

5Verastem Oncology, Needham, United States of America

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1Department of Medicine, Division of Oncology, Washington University School of Medicine, Siteman Cancer Center, St. Louis, United States of America

2Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

3Division of Biological Sciences, Pacific Northwest National Laboratory, Seattle, United States of America

4Department of Radiation Oncology, Mayo Clinic, Rochester, United States of America

5Verastem Oncology, Needham, United States of America

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1Department of Medicine, Division of Oncology, Washington University School of Medicine, Siteman Cancer Center, St. Louis, United States of America

2Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

3Division of Biological Sciences, Pacific Northwest National Laboratory, Seattle, United States of America

4Department of Radiation Oncology, Mayo Clinic, Rochester, United States of America

5Verastem Oncology, Needham, United States of America

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1Department of Medicine, Division of Oncology, Washington University School of Medicine, Siteman Cancer Center, St. Louis, United States of America

2Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

3Division of Biological Sciences, Pacific Northwest National Laboratory, Seattle, United States of America

4Department of Radiation Oncology, Mayo Clinic, Rochester, United States of America

5Verastem Oncology, Needham, United States of America

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1Department of Medicine, Division of Oncology, Washington University School of Medicine, Siteman Cancer Center, St. Louis, United States of America

2Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

3Division of Biological Sciences, Pacific Northwest National Laboratory, Seattle, United States of America

4Department of Radiation Oncology, Mayo Clinic, Rochester, United States of America

5Verastem Oncology, Needham, United States of America

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1Department of Medicine, Division of Oncology, Washington University School of Medicine, Siteman Cancer Center, St. Louis, United States of America

2Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

3Division of Biological Sciences, Pacific Northwest National Laboratory, Seattle, United States of America

4Department of Radiation Oncology, Mayo Clinic, Rochester, United States of America

5Verastem Oncology, Needham, United States of America

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1Department of Medicine, Division of Oncology, Washington University School of Medicine, Siteman Cancer Center, St. Louis, United States of America

2Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

3Division of Biological Sciences, Pacific Northwest National Laboratory, Seattle, United States of America

4Department of Radiation Oncology, Mayo Clinic, Rochester, United States of America

5Verastem Oncology, Needham, United States of America

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1Department of Medicine, Division of Oncology, Washington University School of Medicine, Siteman Cancer Center, St. Louis, United States of America

2Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

3Division of Biological Sciences, Pacific Northwest National Laboratory, Seattle, United States of America

4Department of Radiation Oncology, Mayo Clinic, Rochester, United States of America

5Verastem Oncology, Needham, United States of America

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1Department of Medicine, Division of Oncology, Washington University School of Medicine, Siteman Cancer Center, St. Louis, United States of America

2Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

3Division of Biological Sciences, Pacific Northwest National Laboratory, Seattle, United States of America

4Department of Radiation Oncology, Mayo Clinic, Rochester, United States of America

5Verastem Oncology, Needham, United States of America

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1Department of Medicine, Division of Oncology, Washington University School of Medicine, Siteman Cancer Center, St. Louis, United States of America

2Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

3Division of Biological Sciences, Pacific Northwest National Laboratory, Seattle, United States of America

4Department of Radiation Oncology, Mayo Clinic, Rochester, United States of America

5Verastem Oncology, Needham, United States of America

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1Department of Medicine, Division of Oncology, Washington University School of Medicine, Siteman Cancer Center, St. Louis, United States of America

2Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

3Division of Biological Sciences, Pacific Northwest National Laboratory, Seattle, United States of America

4Department of Radiation Oncology, Mayo Clinic, Rochester, United States of America

5Verastem Oncology, Needham, United States of America

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1Department of Medicine, Division of Oncology, Washington University School of Medicine, Siteman Cancer Center, St. Louis, United States of America

2Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

3Division of Biological Sciences, Pacific Northwest National Laboratory, Seattle, United States of America

4Department of Radiation Oncology, Mayo Clinic, Rochester, United States of America

5Verastem Oncology, Needham, United States of America

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1Department of Medicine, Division of Oncology, Washington University School of Medicine, Siteman Cancer Center, St. Louis, United States of America

2Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

3Division of Biological Sciences, Pacific Northwest National Laboratory, Seattle, United States of America

4Department of Radiation Oncology, Mayo Clinic, Rochester, United States of America

5Verastem Oncology, Needham, United States of America

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1Department of Medicine, Division of Oncology, Washington University School of Medicine, Siteman Cancer Center, St. Louis, United States of America

2Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

3Division of Biological Sciences, Pacific Northwest National Laboratory, Seattle, United States of America

4Department of Radiation Oncology, Mayo Clinic, Rochester, United States of America

5Verastem Oncology, Needham, United States of America

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1Department of Medicine, Division of Oncology, Washington University School of Medicine, Siteman Cancer Center, St. Louis, United States of America

2Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

3Division of Biological Sciences, Pacific Northwest National Laboratory, Seattle, United States of America

4Department of Radiation Oncology, Mayo Clinic, Rochester, United States of America

5Verastem Oncology, Needham, United States of America

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1Department of Medicine, Division of Oncology, Washington University School of Medicine, Siteman Cancer Center, St. Louis, United States of America

2Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

3Division of Biological Sciences, Pacific Northwest National Laboratory, Seattle, United States of America

4Department of Radiation Oncology, Mayo Clinic, Rochester, United States of America

5Verastem Oncology, Needham, United States of America

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1Department of Medicine, Division of Oncology, Washington University School of Medicine, Siteman Cancer Center, St. Louis, United States of America

2Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

3Division of Biological Sciences, Pacific Northwest National Laboratory, Seattle, United States of America

4Department of Radiation Oncology, Mayo Clinic, Rochester, United States of America

5Verastem Oncology, Needham, United States of America

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1Department of Medicine, Division of Oncology, Washington University School of Medicine, Siteman Cancer Center, St. Louis, United States of America

2Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

3Division of Biological Sciences, Pacific Northwest National Laboratory, Seattle, United States of America

4Department of Radiation Oncology, Mayo Clinic, Rochester, United States of America

5Verastem Oncology, Needham, United States of America

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Published August 11, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI201331.
Copyright © 2026, Wang et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published August 11, 2026 - Version history
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Abstract

Aneuploidy is a hallmark of cancer often associated with inferior prognosis. Copy number gains of chromosome 8 (chr8) are recurrent in multiple cancers, including breast, prostate, colorectal cancers, and sarcomas such as malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs are aggressive, hard-to-treat sarcomas frequently linked to the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome. To investigate the role of chr8 gain in MPNST pathogenesis, we performed a CRISPR knockout screen and identified 58 essential genes on chr8, including PTK2, which encodes focal adhesion kinase (FAK). We evaluated FAK as a therapeutic target and tested small-molecule FAK inhibitors (FAKi) alone or combined with RAF/MEK inhibitors (RAF/MEKi), a class of agents relevant to NF1-deficient tumors with ERK pathway hyperactivation. Both pharmacological and genetic inhibition of FAK reduced MPNST cell proliferation in vitro and tumor growth in vivo. Combined FAKi and RAF/MEKi treatment further suppressed phosphorylation of FAK, STAT3, and AKT while increasing cleaved caspase-3 and PARP-1, indicating enhanced apoptosis. In MPNST patient-derived xenograft (PDX) models, combination therapy significantly reduced tumor growth, showing superior efficacy, particularly in chr8 gain MPNST-PDX. These results support FAK/RAF/MEK co-targeting as a promising therapeutic strategy for chr8 gain MPNST and related tumors.

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