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See article, p. 556

Preclinical data indicate that CDK4 inhibition (CDK4i) in combination with MEK inhibition (MEKi) results in a more complete shutdown of NRAS signaling than single-agent MEKi, prompting evaluation of this combination in a phase Ib/II clinical trial of patients with NRAS-mutant melanoma, which achieved promising preliminary results. To identify mechanisms of resistance to this combination therapy, Romano and colleagues performed whole-exome sequencing of five longitudinal biopsies from a patient who initially responded to MEKi plus CDK4i, but eventually developed resistance. Comparison of pre- and post-resistance samples revealed an acquired oncogenic mutation: PI3KCA^E545K. To determine if this mutation may have eluded standard detection methods pretreatment, blocker displacement amplification was used to detect rare variants on multiple regions of the pretreatment tumor. This showed that the PI3KCA^E545K mutation was preexisting, found in only 3 of 7 pretreatment regions as a rare variant, and the PI3KCA^E545K...