TY - JOUR T1 - Combinatorial inhibition of focal adhesion kinase and BCL-2 enhances anti-leukemia activity of venetoclax in acute myeloid leukemia JF - Molecular Cancer Therapeutics JO - Mol Cancer Ther DO - 10.1158/1535-7163.MCT-19-0841 SP - molcanther.0841.2019 AU - Wang, Xiangmeng AU - Mak, Po Yee AU - Mu, Hong AU - Tao, Wenjing AU - Rao, Arvind AU - Visweswaran, Ravikumar AU - Ruvolo, Vivian AU - Pachter, Jonathan A. AU - Weaver, David T. AU - Andreeff, Michael AU - Xu, Bing AU - Carter, Bing Z. Y1 - 2020/01/01 UR - http://mct.aacrjournals.org/content/early/2020/05/13/1535-7163.MCT-19-0841.abstract N2 - Focal adhesion kinase (FAK) promotes cancer cell growth and metastasis. We previously reported that FAK inhibition by the selective inhibitor VS-4718 exerted anti-leukemia activities in 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 pre-existing 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 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 d, 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 d, p = 0.0119). Furthermore, the combination decreased NF-κB signaling and induced the expression of interferon genes in vivo. The combination also markedly extended survival of a second PDX model developed from an aggressive, p53-mutated complex karyotype AML sample. The data suggest that the combined inhibition of FAK and BCL-2 enhances anti-leukemia activity in AML at least in part by suppressing MCL-1 and BCL-XL and that this combination may be effective in AML with p53 and other mutations, and thus benefit high-risk AML patients. ER -