Combinatorial Inhibition of Focal Adhesion Kinase and BCL-2 Enhances Antileukemia Activity of Venetoclax in Acute Myeloid Leukemia

Abstract

Focal adhesion kinase (FAK) promotes cancer cell growth and metastasis. We previously reported that FAK inhibition by the selective inhibitor VS-4718 exerted antileukemia activities in acute myeloid leukemia (AML). The mechanisms involved, and whether VS-4718 potentiates efficacy of other therapeutic agents, have not been investigated. Resistance to apoptosis inducted by the BCL-2 inhibitor ABT-199 (venetoclax) in AML is mediated by preexisting and ABT-199–induced overexpression of MCL-1 and BCL-XL. We observed that VS-4718 or silencing FAK with siRNA decreased MCL-1 and BCL-XL levels. Importantly, VS-4718 antagonized ABT-199–induced MCL-1 and BCL-XL. VS-4718 markedly synergized with ABT-199 to induce apoptosis in AML cells, including primary AML CD34+ cells and AML cells overexpressing MCL-1 or BCL-XL. In a patient-derived xenograft (PDX) model derived from a patient sample with NPM1/FLT3-ITD/TET2/DNMT3A/WT1 mutations and complex karyotype, VS-4718 statistically significantly reduced leukemia tissue infiltration and extended survival (72 vs. control 36 days, P = 0.0002), and only its combination with ABT-199 effectively decreased systemic leukemia tissue infiltration and circulating blasts, and prolonged survival (65.5 vs. control 36 days, P = 0.0119). Furthermore, the combination decreased NFκB signaling and induced the expression of IFN genes in vivo. The combination also markedly extended survival of a second PDX model developed from an aggressive, TP53-mutated complex karyotype AML sample. The data suggest that the combined inhibition of FAK and BCL-2 enhances antileukemia activity in AML at least in part by suppressing MCL-1 and BCL-XL and that this combination may be effective in AML with TP53 and other mutations, and thus benefit patients with high-risk AML.