Endogenous and imposed determinants of apoptotic vulnerabilities in cancer

The intrinsic apoptosis pathway is controlled by the BCL-2 family of proteins. Although the prosurvival members of this family can help cancer cells evade apoptosis, they may also produce apoptotic vulnerabilities that can potentially be exploited therapeutically. Apoptotic vulnerabilities can be driven by endogenous factors, including altered genetics, signaling, metabolism, structure, and lineage or differentiation state, as well as imposed factors, the most prominent being exposure to anticancer agents. The recent development of BH3 mimetics that inhibit prosurvival BCL-2 family proteins has allowed these apoptotic vulnerabilities to be targeted with demonstrable clinical success. Here, we review the key concepts that are vital for understanding, uncovering, and exploiting apoptotic vulnerabilities in cancer for the potential improvement of patient outcomes.

Automated summary

The BCL-2 family of proteins controls the intrinsic apoptosis pathway, which can be targeted therapeutically to exploit apoptotic vulnerabilities in cancer. These vulnerabilities can be driven by various factors, including genetics, signaling, metabolism, structure, lineage, and exposure to anticancer agents. BH3 mimetics that inhibit prosurvival BCL-2 family proteins have shown promising clinical success in targeting these vulnerabilities. This review highlights the key concepts necessary for understanding and exploiting apoptotic vulnerabilities in cancer for improved patient outcomes.