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 5

FAKi enhances the apoptotic effect of a RAF/MEKi in MPNST cells.

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FAKi enhances the apoptotic effect of a RAF/MEKi in MPNST cells. (A) Hea...
(A) Heatmap of synergy scores for cell death in JW23.3, JH-2-002, and WU-356 MPNST cells, generated by using SynergyFinder. Synergy score > 10 indicates synergy. (B) Defactinib enhanced cell death induction when used together with RAF/MEKi avutometinib, using YOYO-1 green fluorescence as an indicator of cell death. The cell death ratio was determined by calculating the number of green dead cells relative to cell confluence per well and normalizing this value to the baseline measurement at time 0. One-way ANOVA with Tukey’s post hoc test was used for multiple-group comparisons. (C) Representative bands of Western blot (Simple WES) assay for total or phosphorylated FAK, AKT, ERK1/2, and STAT3, as well as total or cleaved caspase-3 and PARP-1. GAPDH served as loading control. Avutometinib and defactinib were tested at indicated concentrations. Cell lysates were collected after 48 hours of treatment. WES assays were repeated twice; representative images are shown.