2. Academic Validation
  3. Evolutionary predictability of genetic versus nongenetic resistance to anticancer drugs in melanoma

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

  • Cancer Cell. 2021 Aug 9;39(8):1135-1149.e8. doi: 10.1016/j.ccell.2021.05.015.
Oskar Marin-Bejar 1,  Aljosja Rogiers 1,  Michael Dewaele 1,  Julia Femel 2,  Panagiotis Karras 1,  Joanna Pozniak 1,  Greet Bervoets 1,  Nina Van Raemdonck 1,  Dennis Pedri 1,  Toon Swings 3,  Jonas Demeulemeester 4,  Sara Vander Borght 5,  Stefan Lehnert 6,  Francesca Bosisio 7,  Joost J van den Oord 7,  Isabelle Vanden Bempt 6,  Diether Lambrechts 8,  Thierry Voet 9,  Oliver Bechter 10,  Helen Rizos 11,  Mitchell P Levesque 12,  Eleonora Leucci 13,  Amanda W Lund 2,  Florian Rambow 14,  Jean-Christophe Marine 15
Affiliations

Affiliations

  • 1 Laboratory for Molecular Cancer Biology, Center for Cancer Biology, VIB, Leuven, Belgium; Laboratory for Molecular Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium.
  • 2 Ronald O. Perelman Department of Dermatology and Department of Pathology, NYU Grossman School of Medicine, New York, NY, USA.
  • 3 VIB Technology Watch, Technology Innovation Lab, VIB, Leuven, Belgium.
  • 4 Laboratory of Reproductive Genomics, Department of Human Genetics, KU Leuven, Leuven, Belgium; Cancer Genomic Laboratory, The Francis Crick Institute, London, UK.
  • 5 Department of Pathology, UZ Leuven, Leuven, Belgium.
  • 6 Center for Human Genetics, KULeuven, Leuven, Belgium.
  • 7 Laboratory of Translational Cell and Tissue Research, Department of Pathology, KU Leuven and UZ Leuven, Leuven, Belgium.
  • 8 Laboratory of Translational Genetics, Center for Cancer Biology, VIB, Leuven, Belgium; Laboratory of Translational Genetics, Center for Human Genetics, KU Leuven, Belgium.
  • 9 Laboratory of Reproductive Genomics, Department of Human Genetics, KU Leuven, Leuven, Belgium; KU Leuven Institute for Single Cell Omics, LISCO, KU Leuven, Leuven, Belgium.
  • 10 Department of General Medical Oncology UZ Leuven, Belgium.
  • 11 Macquarie University, Sydney, NSW, Australia; Melanoma Institute Australia, Sydney, NSW, Australia.
  • 12 Department of Dermatology, University of Zürich Hospital, University of Zürich, Zürich, Switzerland.
  • 13 Laboratory for RNA Cancer Biology, Department of Oncology, LKI, KU Leuven, Leuven, Belgium; Trace PDX Platform, Department of Oncology, LKI, KU Leuven, Leuven, Belgium.
  • 14 Laboratory for Molecular Cancer Biology, Center for Cancer Biology, VIB, Leuven, Belgium; Laboratory for Molecular Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium. Electronic address: [email protected].
  • 15 Laboratory for Molecular Cancer Biology, Center for Cancer Biology, VIB, Leuven, Belgium; Laboratory for Molecular Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium. Electronic address: [email protected].
PMID: 34143978 DOI: 10.1016/j.ccell.2021.05.015
Abstract

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.

Keywords

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

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