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

Oskar Marin-Bejar1, Aljosja Rogiers1, Michael Dewaele1

  • 1Laboratory for Molecular Cancer Biology, Center for Cancer Biology, VIB, Leuven, Belgium; Laboratory for Molecular Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium.

Cancer Cell
|June 18, 2021
PubMed

Insights

Melanoma therapy resistance can stem from non-genetic mechanisms involving neural crest stem cell (NCSC) populations. Inhibiting focal adhesion kinase (FAK) in minimal residual disease (MRD) delays relapse and reveals distinct resistance pathways.

Area of Science:

  • Oncology
  • Cancer Biology
  • Melanoma Research

Background:

  • Therapy resistance in cancer, particularly melanoma, is a significant clinical challenge.
  • Resistance can emerge from genetically diverse persister cells or minimal residual disease (MRD) via genetic or non-genetic pathways.
  • Understanding the molecular drivers of MRD is crucial for predicting and overcoming treatment failure.

Purpose of the Study:

  • To investigate whether specific molecular features of the MRD ecosystem dictate the trajectory towards genetic or non-genetic resistance.
  • To identify mechanisms underlying non-genetic resistance in melanoma treated with mitogen-activated protein kinase (MAPK) inhibitors.
  • To explore therapeutic strategies targeting non-genetic resistance to delay or prevent relapse.

Main Methods:

  • Analysis of melanoma minimal residual disease (MRD) following MAPK inhibitor treatment.
  • Investigated the role of neural crest stem cell (NCSC) populations in MRD.
  • Utilized glial cell line-derived neurotrophic factor (GDNF) and AKT pathway signaling.
  • Employed focal adhesion kinase (FAK) inhibition in patient-derived tumor xenografts.
  • Assessed genetic alterations and sensitivity to extracellular signal-regulated kinase (ERK) inhibition in resistant tumors.

Main Results:

  • Emergence of a transient NCSC population in MRD correlated with non-genetic resistance.
  • GDNF signaling activated AKT via FAK, promoting NCSC-mediated resistance.
  • FAK inhibition in MRD delayed tumor relapse in xenografts.
  • Tumors evading FAK inhibition developed genetic alterations and became sensitive to ERK inhibition.

Conclusions:

  • The cellular composition of MRD deterministically influences distinct drug resistance evolutionary paths.
  • Targeting the NCSC population via FAK inhibition offers a strategy to abrogate non-genetic resistance in melanoma.
  • This approach can delay relapse and potentially guide subsequent therapeutic interventions based on emerging resistance mechanisms.
Keywords:
FAK signalingcutaneous melanomaminimal residual diseaseneural crest stem cellsnongenetic reprogrammingpatient-derived tumor xenograftssingle-cell sequencingtherapy resistance

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