A phase 2 study of defactinib (VS-6063), a cancer stem cell inhibitor that acts through inhibition of focal adhesion kinase (FAK), in patients with KRAS-mutant non-small cell lung cancer.

TPS8126 Background: KRAS mutations have been associated with poor prognosis in NSCLC and resistance to epidermal growth factor (EGFR) tyrosine kinase inhibitors. FAK represents a therapeutic target in KRAS mutant NSCLC. The RHOA-FAK axis is a critical downstream mediator of RAS signal transduction and FAK inhibition results in growth suppression in KRAS mutant but not KRAS wild type (wt) cancers both in vitro and in vivo. Interestingly, loss of function of the tumor suppressors CDKN2A/INK4a/ARF (p16) and/or p53 appears requisite for efficacy of FAK inhibition in KRAS-driven cancers. Specifically, in vitro and in vivo studies in xenograft and transgenic KRAS mutant NSCLC adenocarcinoma models carrying INK4a/Arf and/or p53 mutant genotypes demonstrated susceptibility to FAK inhibition evidenced by tumor inhibition and prolonged survival. Furthermore, treatment with FAK inhibitors reduces the proportion of cancer stem cells (CSCs) compared to treatment with standard chemotherapy which enriches for CSCs. Defa...