Abstract This study tested the hypothesis that tumor cells can evade apoptosis following BH3 mimetic treatment by utilizing alternative Bim binding partners. Levels of Bim heterodimers with Mcl-1, Bcl-2 and Bcl-xL were measured in multiple hematologic cell line xenograft models (AMO-1, MV4-11, and RPMI-8226) following single-dose S63845 or venetoclax; Bak—Bax heterodimer and cleaved caspase-3 (cCasp3) levels were measured to demonstrate mitochondrial apoptosis. Anti-tumor efficacies of these agents were measured in vivo in mice bearing AMO-1 or MV4-11 xenografts and in vitro in patient-derived lymphoblastoid-like cells. Mechanism of combination activity of the CDC-like kinase (CLK) inhibitor cirtuvivint with venetoclax was determined in MV4-11 and KG-1a xenografts. S63845 decreased Mcl-1—Bim levels in AMO-1 and MV4-11 tumors by ~90% while unexpectedly decreasing Bcl-2—Bim and increasing Bcl-xL—Bim levels. Venetoclax decreased Bcl-2—Bim levels while increasing Mcl-1—Bim and Bcl-xL—Bim levels in MV4-11 tumors. The S63845+venetoclax combination decreased Mcl-1—Bim levels and demonstrated greater cell killing activity and pharmacodynamic effects than either single agent in multiple models including patient-derived lymphoblastoid-like cells. Cirtuvivint decreased Mcl-1 and Bim levels, combining with venetoclax to induce significantly greater Bak—Bax and cCasp3 responses than either single agent and induced regression of MV4-11 xenograft tumors. Our results elucidate quantitative pharmacodynamics of S63845, venetoclax, and cirtuvivint, an agent that is currently being evaluated with venetoclax to treat AML (NCT06484062). Compensatory increases in off-target Bim heterodimer levels in response to either S63845 or venetoclax offer a possible mechanism of clinical drug resistance.
Govindharajulu et al. (Tue,) studied this question.
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