Combinatorial Inhibition of Focal Adhesion Kinase and BCL-2 Enhances Antileukemia Activity of Venetoclax in Acute Myeloid Leukemia
Focal adhesion kinase (FAK) is a key promoter of cancer cell proliferation and metastasis.
We previously demonstrated that the selective FAK inhibitor VS-4718 exerts antileukemic effects in acute myeloid leukemia (AML). However, the underlying mechanisms and its potential to enhance the efficacy of other therapies remained unexplored.
Resistance to the BCL-2 inhibitor ABT-199 (venetoclax) in AML is commonly mediated by the upregulation of anti-apoptotic proteins MCL-1 and BCL-XL—both preexisting and induced by ABT-199 treatment. In this study, we found that treatment with VS-4718 or FAK knockdown via siRNA significantly reduced MCL-1 and BCL-XL protein levels. Notably, VS-4718 counteracted ABT-199-induced upregulation of these survival proteins.
Importantly, the combination of VS-4718 and ABT-199 synergistically induced apoptosis in AML cells, including primary CD34⁺ AML cells and AML cells with elevated MCL-1 or BCL-XL expression. In a patient-derived xenograft (PDX) model carrying NPM1, FLT3-ITD, TET2, DNMT3A, and WT1 mutations with a complex karyotype, VS-4718 alone significantly reduced leukemic infiltration and improved survival (72 days vs. 36 days for control, P = 0.0002). However, only the combination of VS-4718 and ABT-199 substantially decreased systemic leukemic burden, reduced circulating blasts, and prolonged survival (65.5 vs. 36 days, P = 0.0119).
Mechanistically, the combination therapy suppressed NFκB signaling and upregulated interferon (IFN) pathway gene expression in vivo. In a second PDX model derived from a highly aggressive, TP53-mutated AML with complex karyotype, the combination also led to a significant survival benefit.
Conclusion:
Combined FAK and BCL-2 inhibition enhances antileukemic activity in AML, at least in part through suppression of MCL-1 and BCL-XL. This strategy may be particularly effective in high-risk AML subtypes, including those with TP53 and other adverse mutations, and holds promise for improving outcomes PND-1186 in patients with refractory or poor-prognosis disease.