Melanoma cells exploit both genetic and nongenetic mechanisms of resistance to MAPK inhibition.

  • Major Finding: Melanoma cells exploit both genetic and nongenetic mechanisms of resistance to MAPK inhibition.

  • Concept: Cells persisting during treatment exhibit a neural crest–like state and can be targeted by FAK inhibition.

  • Impact: Resistance to MAPK inhibition is governed by the cellular composition of minimal residual disease.

Resistance to cancer drugs emerging from minimal residual disease (MRD) or drug-tolerant cells happens via both genetic and nongenetic mechanisms. However, little is currently known about the molecular features that determine which of these routes will prevail and lead to relapsed disease. Marin-Bejar, Rogiers, and colleagues analyzed whole-exome sequencing data from 64 BRAF-mutant melanoma samples that progressed after treatment with MAPK pathway inhibitors, finding that 20% of samples contained no known genetic alterations conferring resistance. RNA sequencing of samples from 49 matched untreated and RAF/MEK inhibitor–treated patients with melanoma showed that 28% of patients showed enrichment of a neural crest stem cell (NCSC) signature post-treatment that was present in patients who had partially responded, but absent in nonresponders. BRAF-mutant patient-derived xenograft (PDX) models exposed to MAPK pathway inhibitors initially experienced inhibition of tumor growth, followed by eventual progression. Targeted sequencing of these tumors revealed both genetic and nongenetic drug resistance trajectories, with IHC analysis of key NCSC markers showing no enrichment in lesions from genetic resistance PDXs. Further analysis of the NCSC-like cell population in nongenetic resistance PDXs showed selective activation of focal adhesion kinase (FAK) signaling with GDNF-dependent AKT activation. Treatment of PDX-bearing mice with FAK inhibitors ablated the NCSC population, delaying the emergence of MAPK-therapy resistance and relapse. Sequencing of these samples upon relapse revealed a trajectory switch, with 8 of 9 samples showing the emergence of genetic alterations indicative of reactivation of ERK signaling that conferred increased sensitivity to ERK inhibition compared with MAPK inhibitor–only resistant primary samples. In addition to demonstrating the ability of melanoma cells to evolve genetic and nongenetic pathways of treatment resistance, these findings point to a potential therapeutic approach to target the nongenetic resistance trajectory in melanoma.

Marin-Bejar O, Rogiers A, Dewaele M, Femel J, Karras P, Pozniak J, et al. Evolutionary predictability of genetic versus nongenetic resistance to anticancer drugs in melanoma. Cancer Cell 2021 Jun 17 [Epub ahead of print].

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