Dual-targeting Bcl-2-mediated apoptosis and synergistic pathways: Combinatorial strategies to overcome therapeutic resistance in cancer.

Dysregulation of apoptosis pathways is a defining characteristic of cancer, that has established pro-apoptotic activation as a fundamental therapeutic strategy in oncology. The B-cell lymphoma-2 (Bcl-2) family proteins serves as master regulators of mitochondrial apoptosis, with anti-apoptotic members constituting critical checkpoints in cancer cell survival. Across diverse cancer types, overexpression of anti-apoptotic Bcl-2 proteins is a universal mechanism driving cancer cells to evade apoptosis and acquire resistance to chemotherapy. However, relying solely on agents that induce the downregulation of anti-apoptotic Bcl-2 proteins has proven inefficient for cancer treatment. Notably, the observed synergy between Bcl-2 inhibitors and other anti-tumor agents supports the development of dual-targeting regimens as promising therapeutic approaches. Here, we comprehensively review the recent progress in dual-targeted apoptotic modulation, focusing on strategies that concurrently inhibit anti-apoptotic Bcl-2 family proteins and synergistic pathways. Emerging evidence demonstrates that Bcl-2/B cell lymphoma extra large (Bcl-xL)/myeloid cell leukemia 1 (Mcl-1) inhibitors (e.g., venetoclax and the derivatives) combined with p53/murine double minute 2 (MDM2) disruptors, epigenetic modifiers (e.g., histone deacetylase inhibitors), autophagy modulators, or kinases inhibitors, achieve synergistic potency. These rationally designed combination therapies effectively suppress compensatory upregulation of alternative anti-apoptotic proteins, overcome Bcl-2/Bcl-xL/Mcl-1-driven resistance and restore drug efficacy in apoptosis-deficient cancer subtypes. This paradigm shift offers substantial potential to advance precision oncology by establishing durable responses through simultaneous blockade of multiple survival axes, and carries tremendous promise in the next-generation evolution of cancer therapeutics.