Evolutionary predictability of genetic versus nongenetic resistance to anticancer drugs in melanoma

Oskar Marin-Bejar, Aljosja Rogiers, Michael Dewaele, Julia Femel, Panagiotis Karras, Joanna Pozniak, Greet Bervoets, Nina Van Raemdonck, Dennis Pedri, Toon Swings, Jonas Demeulemeester, Sara Vander Borght, Stefan Lehnert, Francesca Bosisio, Joost J. van den Oord, Isabelle Vanden Bempt, Diether Lambrechts, Thierry Voet, Oliver Bechter, Helen RizosMitchell P. Levesque, Eleonora Leucci, Amanda W. Lund, Florian Rambow*, Jean Christophe Marine

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

64 Citations (Scopus)


Therapy resistance arises from heterogeneous drug-tolerant persister cells or minimal residual disease (MRD) through genetic and nongenetic mechanisms. A key question is whether specific molecular features of the MRD ecosystem determine which of these two distinct trajectories will eventually prevail. We show that, in melanoma exposed to mitogen-activated protein kinase therapeutics, emergence of a transient neural crest stem cell (NCSC) population in MRD concurs with the development of nongenetic resistance. This increase relies on a glial cell line-derived neurotrophic factor-dependent signaling cascade, which activates the AKT survival pathway in a focal adhesion kinase (FAK)-dependent manner. Ablation of the NCSC population through FAK inhibition delays relapse in patient-derived tumor xenografts. Strikingly, all tumors that ultimately escape this treatment exhibit resistance-conferring genetic alterations and increased sensitivity to extracellular signal-regulated kinase inhibition. These findings identify an approach that abrogates the nongenetic resistance trajectory in melanoma and demonstrate that the cellular composition of MRD deterministically imposes distinct drug resistance evolutionary paths.

Original languageEnglish
Pages (from-to)1135-1149.e8
Number of pages24
JournalCancer Cell
Issue number8
Publication statusPublished - 9 Aug 2021


  • cutaneous melanoma
  • FAK signaling
  • minimal residual disease
  • neural crest stem cells
  • nongenetic reprogramming
  • patient-derived tumor xenografts
  • single-cell sequencing
  • therapy resistance


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