Although RAS is one of the most commonly mutated genes in cancer, targeting RAS has proved difficult, leading to the development of therapies targeting downstream effectors in the MAPK signaling pathway, such as MEK. While MEK inhibitors have had limited clinical success as a monotherapy, preclinical synthetic lethality studies demonstrated that loss of the antiapoptotic protein BCL-xL acts synergistically with MEK inhibition in KRAS-mutant cancers. In this phase I/II study, Corcoran and colleagues investigate the safety and activity of the BCL-xL inhibitor navitoclax combined with the MEK inhibitor trametinib in patients with RAS-mutant colorectal, pancreatic, gynecologic, non-small cell lung cancer, and other cancers. At the established recommended phase II dose, the treatment was tolerable, and 16% of evaluable patients achieved partial response (PR). Patients with gynecologic cancers demonstrated more favorable responses, with 33% of patients achieving PR. Additionally, it was found that reductions in KRAS/NRAS mutation levels in cell free...

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