Understanding the Functional Dependence and Inhibition of the Bcl-2 Pro-Survival Proteins in a Wide Spectrum of Cancers toward Precision Medicine

Introducing and integrating functional assays into clinical cancer care can further enhance the effectiveness of precision cancer medicine. Bcl-2 pro-survival proteins have emerged as promising targets across various cancers, with Venetoclax, a highly selective Bcl-2 inhibitor, being the first approved drug of this category. This study aims to explore BH3 profiling as a functional diagnostic to distinguish pro-survival dependence in a variety of human cancers to identify antiapoptotic Bcl-2 family protein dependencies and sensitivity to BH3 mimetics. The obtained results demonstrate that, in general, hematological cancer cell lines are sensitive to Bcl-2 or Mcl-1 inhibitors. Notably, certain lymphoma subtypes of B-cell and T-cell origin show preferential dependence on Bcl-2 and Mcl-1, respectively. These conclusions were supported and enhanced by follow-up studies of primary patient-derived samples. Immunohistochemistry of patient specimens supported the identified overexpression and functional involvement of Bfl-1 in T-cell lymphomas, highlighting a new potential precision therapy opportunity. Functional profiling of various solid tumor cell lines, including ovarian cancer PDX models, revealed that most solid tumors have a dependence on a combination of Bcl-2 family antiapoptotic proteins. Treatment with a combination of Bcl-xL and Mcl-1 inhibitors induced significant apoptosis in a majority of the tested solid tumor cell lines. The results of this study reveal a functional dependence on Bcl-2 antiapoptotic proteins in various cancers and offer more tailored strategies for utilizing BH3 mimetics in precision cancer therapy.