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KRAS and NRAS Translation Is Increased upon MEK Inhibitors-Induced Processing Bodies Dissolution

Olivia Vidal-Cruchez1,2, Victoria J Nicolini1,2, Tifenn Rete1,2

  • 1Université Côte d'Azur, Institute of Research on Cancer and Aging of Nice (IRCAN), CNRS, INSERM, Centre Antoine Lacassagne, 28, Avenue de Valombrose, 06107 Nice, France.

Cancers
|June 28, 2023
PubMed

Insights

Mitogen-activated protein kinase (MAPK) pathway inhibitors increase RAS oncogene translation by dissolving processing body (P-body) biocondensates, leading to cancer drug resistance. This reveals a new feedback loop in MAPK signaling.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Cell Biology

Background:

  • Mitogen-activated protein kinase (MAPK) pathway overactivation drives many human cancers.
  • Cancer drug resistance arises from therapies targeting this pathway, often linked to compensatory RAS overexpression.
  • Mechanisms underlying RAS overexpression and subsequent drug resistance remain unclear.

Purpose of the Study:

  • To investigate the mechanisms by which MEK inhibitors (MEKi) lead to cancer drug resistance.
  • To elucidate the role of RAS oncogene translation in MAPK pathway signaling and resistance.
  • To identify novel feedback loops regulating RAS protein expression and MAPK pathway activity.

Main Methods:

  • Utilized cell culture models across different cell types.
  • Administered MEK inhibitors (MEKi) and monitored KRAS and NRAS oncogene translation.
  • Investigated the role of processing body (P-body) biocondensates and their scaffold proteins.
  • Assessed the dynamic changes in P-bodies and RAS signaling upon MEKi removal and ERK reactivation.

Main Results:

  • MEK inhibitors (MEKi) increase KRAS and NRAS oncogene translation via P-body biocondensate dissolution.
  • This effect is dynamic, with P-bodies reforming and RAS signaling decreasing upon MEKi withdrawal.
  • Lower levels of P-body scaffold proteins correlate with increased RAS expression.
  • A novel feedback loop involving P-bodies in RAS translational regulation and MAPK signaling is identified.

Conclusions:

  • Dissolution of P-body biocondensates is a key mechanism driving RAS overexpression and subsequent cancer drug resistance.
  • Targeting this P-body-mediated translational control offers a potential strategy to overcome resistance to MAPK-targeted therapies.
  • This study uncovers a new layer of regulation in RAS-MAPK signaling, with implications for cancer treatment.
Keywords:
MEK inhibitorsRAS oncogenic signalingRNA metabolismliquid–liquid phase separationtranslation regulation

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