Adaptive Resistance to Chemotherapy, A Multi-FAK-torial Linkage.

Oncogenes provide tumor cells with a growth and survival advantage. Directed therapies targeted to oncogenic mutations (such as V600E) are part of effective late-stage melanoma treatment. However, tumors with V600E mutations, in approximately 10% of colorectal cancer, are generally treatment-insensitive. Research has identified various "feedback" mechanisms that result in BRAF signal pathway reactivation in response to BRAF inhibition. Herein, we highlight key findings from Chen and colleagues (this issue) showing that integrin-associated focal adhesion kinase (FAK) activation selectively occurs in V600E-mutant colorectal cancer cells in response to pharmacological BRAF inhibition. FAK activation results in elevated β-catenin protein levels, β-catenin nuclear localization, and increased gene transcription. Small-molecule inhibitors of β-catenin or FAK synergize with vemurafenib BRAF inhibitor to prevent V600E colorectal cancer cell proliferation and xenograft tumor growth in mice. This study complements findings linking FAK to β-catenin in intestinal tumorigenesis, resistance to radiotherapy, and cancer stem cell survival. Thus, FAK activation may occur as a frequent tumor cell "adaptive resistance" mechanism. Although FAK () is not mutated in most cancers, targeting FAK activity in combinational approaches may limit tumor cell escape mechanisms and enhance durable responses to treatment. .