Targeting protein-protein interactions in the BCL-2 family: opportunities for precision oncology.

Apoptosis plays a pivotal role in the biological process that responds to cellular oxidative stress and significantly contributes to cancer pathogenesis, thereby altering the efficacy of modern cytotoxic treatments. The B-cell lymphoma 2 (BCL-2) protein family exhibits both pro-apoptotic and anti-apoptotic activities that regulate the intrinsic apoptotic pathway. BCL-2 family members, including pro-apoptotic and pro-survival proteins, are highly expressed or dysregulated in cancer cells, thereby promoting tumor progression and therapeutic resistance. This review systematically summarizes the structural organization, molecular functions, and therapeutic significance of the BCL-2 family in cancer. Furthermore, we critically discuss the active role of the BCL-2 family in modulating apoptosis and evaluate recent advances in the development of BH3 mimetics (Venetoclax (ABT-199), Navitoclax (ABT-263), Obatoclax (GX15-070)) and other BCL-2-targeted therapies. The review also highlights emerging mechanisms of drug resistance, including compensatory MCL-1 overexpression, and discusses current combination therapeutic strategies to overcome resistance. The available preclinical and clinical evidence denotes the therapeutic potential of the BCL-2 family as a promising target for cancer treatment. The single- and combined therapy with Venetoclax, a selective BCL-2 BH3 mimetic, has demonstrated higher efficacy and improved safety compared with conventional therapies and has been successfully applied across distinct cancer types. Finally, we discuss current challenges, including resistance mechanisms and treatment-related toxicities, and outline future directions focusing on biomarker-guided patient stratification and next-generation BCL-2-targeted therapeutics.