Citations 1
Combined FAK and MEK inhibition suppresses chromosome 8 gain malignant peripheral nerve sheath tumors
Wang, Guangfeng , Wang, Jiawan , Zhang, Xiaochun, Yang, Liuzhan , Oztosun, Gorkem, Sears, James J., Xiao, Ke , Garana, Belinda B., Zoberi, Mark I., Bektas, Aaron U., Coma, Silvia, Pachter, Jonathan A. , Gosline, Sara JC, Pratilas, Christine A. , Szymanski, Jeffrey J. , Borcherding, Dana C. , Zhang, Xiaochun, Oztosun, Gorkem , Sears, James J. , Garana, Belinda B. , Rathore, Richa , Coma, Silvia, Gosline, Sara J.C. , Hirbe, Angela C.
Journal of Clinical Investigation | August 11, 2026 | Volume: No volume available | Issue: No issue available | Pages: No page available
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.