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 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 þ 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 ¼ 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 ¼ 0.0119). Furthermore, the combination decreased NFkB 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.

Synergistic Effect of Chidamide and Venetoclax on Apoptosis in Acute Myeloid Leukemia Cells and Its Mechanism

“…Mcl-1 are also downstream of PI3K/AKT pathway, which are frequently constitutively activated in AML [9,48] The PI3K/AKT signaling pathway plays a key role in tumor occurrence, development and radiation resistance; is involved in various cellular activities and metabolic regulation; and is closely related to the proliferation and apoptosis, cell cycle regulation, angiogenesis and invasion and metastasis of cancer cells. The PI3K/AKT pathway inhibits apoptosis through a variety of mechanisms [49] .…”

“…The 5-year overall survival rate of AML is only approximately 25% [4] . Pre-clinical and clinical studies have demonstrated that the selective and highly potent Bcl-2 inhibitor venetoclax has anti-leukemia activities against various hematological malignancies, including MDS, CLL, and AML [5][6][7][8][9] . Venetoclax is FDA approved for a subset of patients with CLL and AML [10,11] .…”

“…Venetoclax is FDA approved for a subset of patients with CLL and AML [10,11] . The FDAapproved combination of venetoclax with decitabine or azacitidine is resulting in CR/CRi rates of 70-95% and good tolerability in elderly AML patients, but patients invariably relapse [9,12,13] . Resistance to apoptosis inducted by venetoclax in AML is mediated by pre-existing and venetoclax-induced overexpression of Mcl-1 [9] .…”

Synergistic effect of chidamide and venetoclax on apoptosis in acute myeloid leukemia cells and its mechanism

“…Pre-clinical and clinical studies have demonstrated that the selective and highly potent Bcl-2 inhibitor venetoclax has anti-leukemia activities against various hematological malignancies, including myelodysplastic syndrome (MDS), chronic lymphocytic leukemia (CLL), and AML (4)(5)(6)(7)(8). Venetoclax is FDA approved for a subset of patients with CLL and AML (9,10), and the FDA-approved combination of venetoclax with decitabine or azacitidine is resulting in CR/complete response with incomplete hematologic recovery (CRi) rates of 70-95% and good tolerability in elderly AML patients, although patients invariably relapse (8,11,12). Resistance to apoptosis inducted by venetoclax in AML is mediated by pre-existing and venetoclax-induced overexpression of Mcl-1 (8), and the overexpression of Mcl-1 has been reported in AML at relapse (13).…”

“…Venetoclax is FDA approved for a subset of patients with CLL and AML (9,10), and the FDA-approved combination of venetoclax with decitabine or azacitidine is resulting in CR/complete response with incomplete hematologic recovery (CRi) rates of 70-95% and good tolerability in elderly AML patients, although patients invariably relapse (8,11,12). Resistance to apoptosis inducted by venetoclax in AML is mediated by pre-existing and venetoclax-induced overexpression of Mcl-1 (8), and the overexpression of Mcl-1 has been reported in AML at relapse (13). The mechanism by which Mcl-1 blocks the progression of apoptosis is through binding and sequestering the pro-apoptotic BH3-only proteins Bim, PUMA, Noxa, Bak, and Bax (14), preventing pore formation on the mitochondrial membrane and the release of cytochrome c into the cytoplasm (15).…”