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

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

  • Cell Rep. 2023 May 29;42(6):112570. doi: 10.1016/j.celrep.2023.112570.
Sungsoo Kim 1 Richard Carvajal 2 Minah Kim 3 Hee Won Yang 4
Affiliations

Affiliations

  • 1 Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
  • 2 Department of Medicine, Columbia University, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA.
  • 3 Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA.
  • 4 Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA. Electronic address: hy2602@cumc.columbia.edu.
Abstract

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 emergence 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 analysis reveals that only a small subset of melanoma cells exhibits effective RTK and ERK activation and develops 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 activation 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, suggesting potential strategies for overcoming drug resistance in BRAF-mutant melanoma.

Keywords

BRAF; CP: Cancer; ERK; RTK; melanoma; persister cells; signaling dynamics.

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