Article Targeting MCL-1 triggers DNA damage and an anti-proliferative response independent from apoptosis induction

MCL-1 is a high-priority target due to its dominant role in the pathogenesis and chemoresistance of cancer, yet clinical trials of MCL-1 inhibitors are revealing toxic side effects. MCL-1 biology is complex, extending beyond apoptotic regulation and confounded by its multiple isoforms, its domains of unresolved structure and function, and challenges in distinguishing noncanonical activities from the apoptotic response. We find that, in the presence or absence of an intact mitochondrial apoptotic pathway, genetic deletion or pharmacologic targeting of MCL-1 induces DNA damage and retards cell proliferation. Indeed, the cancer cell susceptibility profile of MCL-1 inhibitors better matches that of anti-proliferative than pro-apoptotic drugs, expanding their potential therapeutic applications, including synergistic combinations, but heightening therapeutic window concerns. Proteomic profiling provides a resource for mechanistic dissection and reveals the minichromosome maintenance DNA helicase as an interacting nuclear protein complex that links MCL-1 to the regulation of DNA integrity and cell-cycle progression.

Automated summary

MCL-1 plays a dominant role in cancer pathogenesis and chemoresistance, but its inhibitors have toxic side effects in clinical trials. MCL-1 biology is complex, involving multiple isoforms, unresolved structure and function, and challenges in distinguishing noncanonical activities from apoptotic response. Deletion or targeting of MCL-1 induces DNA damage and inhibits cell proliferation. MCL-1 inhibitors have potential therapeutic applications as anti-proliferative drugs, but the therapeutic window concerns need to be addressed.