Issues

Combination therapies targeting MEK and CDK4/6 are under investigation for the treatment of patients with melanoma, but optimal dosing schedules and potential mechanisms of resistance have not been determined. Teh and colleagues found that continuous MEK inhibition (MEKi) with intermittent CDK4/6 inhibition (CDK4/6i) resulted in maximal antitumor activity with limited toxicity. Acquired resistance to MEKi plus CDK4/6i was linked to increased S6 phosphorylation, and an mTORC inhibitor overcame resistance in vivo. Similarly, Romano and colleagues investigated mechanisms of resistance to MEKi plus CDK4i in NRAS-mutant melanoma and uncovered a rare preexisiting mutation (PI3KCA^E545K) that activated S6K1 to increase S6 phosphorylation and promote resistance to MEKi plus CDK4i. Collectively, these findings suggest that mTORC inhibiton may overcome acquired resistance to MEKi plus CDK4i. For details, please see the articles by Teh and colleagues on page 568 and Romano and colleagues on page 556.