Combined FAK and MEK inhibition suppresses chromosome 8 gain malignant peripheral nerve sheath tumors
Guangfeng Wang, Dana C. Borcherding, Jiawan Wang, Xiaochun Zhang, Liuzhan Yang, Gorkem Oztosun, James J. Sears, Kangwen Xiao, Belinda B. Garana, Mark I. Zoberi, Aaron U. Bektas, Jeffrey J. Szymanski, Richa Rathore, Silvia Coma, Jonathan A. Pachter, Sara J.C. Gosline, Christine A. Pratilas, Angela C. Hirbe
Guangfeng Wang, Dana C. Borcherding, Jiawan Wang, Xiaochun Zhang, Liuzhan Yang, Gorkem Oztosun, James J. Sears, Kangwen Xiao, Belinda B. Garana, Mark I. Zoberi, Aaron U. Bektas, Jeffrey J. Szymanski, Richa Rathore, Silvia Coma, Jonathan A. Pachter, Sara J.C. Gosline, Christine A. Pratilas, Angela C. Hirbe
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Research Article Cell biology Oncology

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

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, and 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 poly (ADP-ribose) polymerase 1 (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 cotargeting as a promising therapeutic strategy for chr8 gain MPNST and related tumors.

Authors

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

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Figure 6

Combination of FAKi with RAF/MEKi decreases tumor growth in chr8 gain PDX mouse models.

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Combination of FAKi with RAF/MEKi decreases tumor growth in chr8 gain PD...
(A) MN2 MPNST PDX tumors (n = 6 per group); (B) WU-225 MPNST PDX tumors (n = 7 per group). Mice were treated once daily with 0.3 mg/kg avutometinib (A), twice daily with 50 mg/kg VS-4718 (VS), the combination of drugs, or vehicle control for 4–5 weeks. Gray area indicates treatment period. One-way ANOVA with Tukey’s post hoc test was used for multiple-group comparisons, and Student’s t test was used for comparisons between 2 groups. *P < 0.05, **P < 0.01, ***P < 0.001 vs. vehicle control; ††P < 0.01, †††P < 0.001, for drug combination vs. VS-4718; #P < 0.05, ##P < 0.01, ###P < 0.001 for drug combination vs. avutometinib. (C) Histological (H&E) and immunohistochemical (Ki67, p-FAK, p-AKT, p-ERK, p-STAT3, and cleaved caspase-3) staining of MN2 tumor tissues after 10 days of treatment. Scale bar, 50 μm. (D) In quantification of IHC staining, increased p-FAK and p-AKT were observed after treatment of avutometinib, while the combination with VS-4718 inhibited activity of both FAK and MEK pathways and induced apoptosis. One-way ANOVA with Tukey’s post hoc test was used for multiple-group comparisons, and Student’s t test was used for comparisons between 2 groups. (E) Mechanistic model to explain the combination benefit of FAK and RAF/MEK inhibition in NF1-MPNST with chr8 gain. The red arrow indicates the effect of the RAF/MEKi, the blue arrow shows the effect of the FAKi, and the purple arrow represents the combination effect. Created in BioRender. Hirbe, A. (2026) https://BioRender.com/aerpo6u po, orally; bid, twice daily; qd, once daily.