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CRISPR screens identify tumor-promoting genes conferring melanoma cell plasticity and resistance

Arthur Gautron1, Laura Bachelot1, Marc Aubry1,2

  • 1CNRS, IGDR (Institut de génétique et développement de Rennes)-UMR 6290, Univ Rennes, Rennes, France.

EMBO Molecular Medicine
|March 16, 2021
PubMed

Insights

Non-genetic factors drive melanoma resistance to targeted therapy. Researchers identified SMAD3, BIRC3, and SLC9A5 as key players, with SMAD3 targeting offering a potential new treatment strategy.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Genetic alterations driving melanoma and targeted therapy resistance are largely understood.
  • Non-genetic mechanisms contributing to melanoma progression and drug resistance remain poorly characterized.

Purpose of the Study:

  • To identify non-genetic factors involved in BRAF inhibitor (BRAFi) resistance in melanoma.
  • To explore novel therapeutic targets for overcoming melanoma treatment resistance.

Main Methods:

  • In vivo gain-of-function CRISPR screens were employed to identify key genes.
  • Expression levels of identified genes (SMAD3, BIRC3, SLC9A5) were analyzed during BRAFi resistance acquisition, in persister cells, and during relapse.
  • The role of SMAD3 transcriptional activity (SMAD3-signature) in promoting a mesenchymal-like phenotype and resistance was investigated.
  • The predictive value of the SMAD3-signature for melanoma therapy resistance was assessed in patient cohorts.
  • The efficacy of SMAD3 inhibition and Aryl hydrocarbon Receptor (AhR) inhibition on melanoma cell survival was evaluated.

Main Results:

  • SMAD3, BIRC3, and SLC9A5 were identified as key mediators of BRAFi resistance.
  • Increased expression and activity of SMAD3 were observed during BRAFi resistance, in persister cells, and upon relapse.
  • The SMAD3-signature was found to drive a mesenchymal-like phenotype and BRAFi resistance by regulating genes like EGFR and AXL.
  • The SMAD3-signature accurately predicted resistance to melanoma therapies across different patient cohorts.
  • Chemical inhibition of SMAD3 effectively reduced persister cell survival.
  • Inhibition of Aryl hydrocarbon Receptor (AhR) decreased SMAD3 activity.

Conclusions:

  • Non-genetic mechanisms, particularly involving SMAD3, play a critical role in melanoma BRAFi resistance.
  • Targeting SMAD3 or AhR presents a promising therapeutic strategy to overcome melanoma drug resistance and improve long-term treatment outcomes.
  • The study identifies novel drug vulnerabilities for developing more effective and durable antimelanoma therapies.
Keywords:
Aryl hydrocarbon ReceptorCRISPR-SAMSMAD3melanomatargeted therapy resistance

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