DDDR-59. Focal Adhesion Kinase (FAK) Inhibitor Synergizes with RAF/MEK inhibitor in Malignant Peripheral Nerve Sheath Tumors with Chromosome 8 Gain

Abstract OBJECTIVES Aneuploidy is a common hallmark of cancer and associated with worse prognosis. Gain of chromosome 8 (Chr8) is a common genetic alteration in various cancers, including breast, prostate, colorectal, and malignant peripheral nerve sheath tumors (MPNST). MPNST are aggressive sarcomas often associated with Neurofibromatosis type 1 (NF1), a genetic cancer predisposition syndrome driven by overactivation of the RAS/MAPK pathway. Our lab previously utilized a Chr8 gRNA screen to identify 58 genes essential for survival, including PTK2. PTK2 encodes focal adhesion kinase (FAK), a protein frequently overexpressed in cancer and which is targetable with small molecule inhibitors. METHODS We evaluated the efficacy of PTK2 shRNA knockdown or a FAK inhibitor (FAKi), alone or combined with the RAF/MEK inhibitor avutometinib (RAF/MEKi), in MPNST cells using IncuCyte Live-Cell proliferation and cell death assays. Synergy was determined by SynergyFinder software. Protein expression of FAK and its downstream targets were assessed by Wes SimpleWestern™ analyses. The efficacy of a FAKi, both as a monotherapy and in combination with a RAF/MEKi, was evaluated in patient-derived xenograft (PDX) mouse models of MPNST with and without Chr8 gain. RESULTS Knockdown of PTK2 expression reduced proliferation of MPNST cells. Pharmacological inhibition of FAK by defactinib decreased cell proliferation and increased cell death in three MPNST cell-lines, with concurrent suppression of FAK, STAT3, and AKT phosphorylation. The combination of FAKi and RAF/MEKi showed additive or synergistic effects, suppressing FAK, STAT3, and AKT activation and enhancing cleavage of caspase-3 and PARP-1, in MPNST cell-lines. Finally, FAKi and RAF/MEKi combination significantly decreased tumor growth compared to either drug alone in Chr8-gain, but not Chr8-WT, MPNST-PDX mouse models. CONCLUSION These findings support the co-targeting of FAK and RAF/MEK as a promising therapeutic approach for Chr8-gain tumors in MPNST.