Tyrosine Kinase Inhibitors Increase MCL1 Degradation and in Combination with BCLXL/BCL2 Inhibitors Drive Prostate Cancer Apoptosis.

ABSTRACT: Purpose: Clinically available BH3 mimetic drugs targeting BCLXL and/or BCL2 (navitoclax and venetoclax, respectively) are effective in some hematologic malignancies, but have limited efficacy in solid tumors. This study aimed to identify combination therapies that exploit clinical BH3 mimetics for prostate cancer.Experimental Design: Prostate cancer cells or xenografts were treated with BH3 mimetics as single agents or in combination with other agents, and effects on MCL1 and apoptosis were assessed. MCL1 was also targeted directly using RNAi, CRISPR, or an MCL1-specific BH3 mimetic, S63845.Results: We initially found that MCL1 depletion or inhibition markedly sensitized prostate cancer cells to apoptosis mediated by navitoclax, but not venetoclax, in vitro and

SUBMITTER: Arai S 

PROVIDER: S-EPMC6214713 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature