Abstract

<div>Abstract<p>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<sup>+</sup> cells and AML cells overexpressing MCL-1 or BCL-XL. In a patient-derived xenograft (PDX) model derived from a patient sample with <i>NPM1/FLT3-ITD/TET2/DNMT3A/WT1</i> mutations and complex karyotype, VS-4718 statistically significantly reduced leukemia tissue infiltration and extended survival (72 vs. control 36 days, <i>P</i> = 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, <i>P</i> = 0.0119). Furthermore, the combination decreased NFκB signaling and induced the expression of IFN genes <i>in vivo</i>. The combination also markedly extended survival of a second PDX model developed from an aggressive, <i>TP53</i>-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 <i>TP53</i> and other mutations, and thus benefit patients with high-risk AML.</p></div>

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