Kinetics of RTK activation determine ERK reactivation and resistance to dual BRAF/MEK inhibition in melanoma

The combination of BRAF and MEK inhibitors (BRAFi/MEKi) has shown promising response rates in treating BRAF-mutant melanoma by inhibiting ERK activation. However, treatment efficacy is limited by the emer-gence of drug-tolerant persister cells (persisters). Here, we show that the magnitude and duration of receptor tyrosine kinase (RTK) activation determine ERK reactivation and persister development. Our single-cell anal-ysis reveals that only a small subset of melanoma cells exhibits effective RTK and ERK activation and de-velops persisters, despite uniform external stimuli. The kinetics of RTK activation directly influence ERK signaling dynamics and persister development. These initially rare persisters form major resistant clones through effective RTK-mediated ERK activation. Consequently, limiting RTK signaling suppresses ERK acti-vation and cell proliferation in drug-resistant cells. Our findings provide non-genetic mechanistic insights into the role of heterogeneity in RTK activation kinetics in ERK reactivation and BRAFi/MEKi resistance, suggest-ing potential strategies for overcoming drug resistance in BRAF-mutant melanoma.

Automated summary

The combination of BRAF and MEK inhibitors has shown promise in treating BRAF-mutant melanoma, but drug-tolerant persister cells limit treatment efficacy. RTK activation plays a key role in ERK reactivation and persister development.