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KRAS mutants confer platinum resistance by regulating ALKBH5 posttranslational modifications in lung cancer

Fang Yu1,2, Shikan Zheng3, Chunjie Yu1,2

  • 1Department of Medicine, University of Florida Health Cancer Center and.

The Journal of Clinical Investigation
|February 17, 2025
PubMed

Insights

KRAS mutations in non-small cell lung cancer (NSCLC) drive platinum chemotherapy resistance by increasing DNA repair via m6A methylation. Inhibiting this pathway sensitizes resistant NSCLC cells to platinum drugs.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Constitutively active KRAS mutations are common in non-small cell lung cancer (NSCLC).
  • The mechanisms linking KRAS mutations to platinum chemotherapy resistance are not fully understood.
  • Understanding these mechanisms is crucial for developing effective NSCLC treatments.

Purpose of the Study:

  • To investigate how KRAS mutations confer resistance to platinum-based chemotherapy in NSCLC.
  • To elucidate the molecular mechanisms underlying KRAS-mediated platinum resistance.
  • To identify potential therapeutic targets for overcoming chemoresistance in KRAS-mutant NSCLC.

Main Methods:

  • Investigated the role of KRAS mutations in platinum resistance in NSCLC cell lines.
  • Analyzed the involvement of ERK/JNK signaling and AlkB homolog 5 (ALKBH5) posttranslational modifications (PTMs).
  • Assessed the impact of m6A methylation on DNA repair genes (DDB2, XPC) and nucleotide excision repair.
  • Evaluated the efficacy of inhibiting m6A methylation (ALKBH5 mutant, METTL3 inhibition) in vitro and in vivo.

Main Results:

  • KRAS mutants activate ERK/JNK signaling, inhibiting ALKBH5 demethylase activity through PTMs.
  • This leads to increased m6A methylation of DDB2 and XPC mRNA, enhancing DNA repair and promoting platinum resistance.
  • Overexpressing a SUMOylation-deficient ALKBH5 mutant or inhibiting METTL3 sensitizes KRAS-mutant NSCLC cells to platinum drugs.
  • These findings were validated in both in vitro and in vivo models.

Conclusions:

  • KRAS mutations mediate platinum resistance in NSCLC by activating DNA repair pathways through the ERK/JNK/ALKBH5/m6A axis.
  • Targeting m6A methylation represents a promising strategy to overcome chemoresistance in KRAS-mutant NSCLC.
  • This study reveals a novel mechanism of chemoresistance and a potential therapeutic vulnerability in NSCLC.
Keywords:
Cell biologyEpigeneticsLung cancerOncologySignal transduction

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