Combined MEK and BCL-XL Inhibition Kills KRAS-Mutant Cells

Activating mutations in KRAS are among the most common genetic events in human cancers. Strategies to treat KRAS-mutant cancers are urgently needed because KRAS remains an intractable drug target. Preclinical studies have indicated that inhibition of MEK, a key KRAS effector, potently suppresses proliferation of KRAS-mutant cancer cells, but these cytostatic effects have not translated into clinical responses in patients with KRAS-mutant tumors. Based on the premise that the complexity of KRAS signaling may require simultaneous targeting of more than one effector pathway, Corcoran and colleagues screened a small hairpin RNA (shRNA) library targeting druggable genes for those that cooperated with selumetinib and other MEK inhibitors to selectively reduce the viability of KRAS-mutant cell lines. The top scoring gene was BCL2L1, encoding the antiapoptotic BH3 family member BCL-XL. The combination of selumetinib and navitoclax, a clinically available BH3 mimetic that inhibits the prosurvival function of BCL-XL by blocking its ability to bind and sequester proapoptotic proteins, had a significantly greater effect on proliferation and survival of KRAS-mutant cell lines than either agent did alone. Levels of the proapoptotic protein BIM increased in response to selumetinib, along with a proportional increase in the amount of BCL-XL bound to BIM, suggesting that suppression of prosurvival molecules such as BCL-XL can induce cell death in response to selumetinib by freeing BIM from inhibition. Indeed, navitoclax completely blocked the interaction between BIM and BCL-XL in selumetinib-treated cells, and combined use of selumetinib and navitoclax induced significant tumor regression in KRAS-driven mouse cancer models. Together, these findings suggest that combined inhibition of BCL-XL and MEK may be effective in KRAS-mutant cancers and underscore the therapeutic potential of augmenting the effects of targeted therapies with potentiators of apoptosis.

Corcoran RB, Cheng KA, Hata AN, Faber AC, Ebi H, Coffee EM, et al. Synthetic lethal interaction of combined BCL-XL and MEK inhibition promotes tumor regressions in KRAS mutant cancer models. Cancer Cell 2013;23:121–8.

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