More of the Same — Mechanisms of Resistance to Combined BRAF and MEK Inhibitors

Strategies to combat drug-resistant melanoma are urgently needed. Resistance to BRAF inhibitors (BRAFi) often involves re-engagement of the RAF-MEK signaling pathway that converges on ERK. Multiple clinical trials show that combined BRAF and MEK inhibition confers greater survival than either alone.

Using a series of matched patient samples from patients before and after progression on combination therapy, Moriceau and colleagues identified mechanisms previously shown to be important in BRAFi resistance, including NRAS mutation, BRAF ultra-amplification (>74 copies), altered BRAF splicing, and the loss of the tumor suppressors PTEN and CDKN2A. Resistance evolved in BRAF-mutant melanoma cells exposed to BRAFi/MEKi. The mechanisms of resistanc…