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EML4-ALK mediates resistance to KRAS G12C inhibition and induces an oncogenic dependency by rewiring signaling

Pietro Scaparone1, Alessia Mira1, Taek-Chin Cheong2

  • 1University of Turin Turin, TO Italy.

Cancer Discovery
|June 22, 2026
PubMed

Insights

KRASG12C inhibitors show limited efficacy in lung cancer due to resistance. This study reveals acquired EML4-ALK fusion as a resistance mechanism, suggesting combined ALK/KRASG12C inhibition or sequential treatments as effective strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • KRAS mutations drive many human cancers, with KRASG12C being a significant target in lung adenocarcinoma (LUAD).
  • KRASG12C inhibitors have FDA approval, but clinical efficacy is hampered by modest response rates and acquired resistance.
  • Genomic alterations, such as EML4-ALK fusion, can emerge as resistance mechanisms in KRASG12C-driven tumors.

Purpose of the Study:

  • To investigate the mechanisms of acquired EML4-ALK fusion in KRASG12C-mutant LUAD developing resistance to KRASG12C inhibitors.
  • To explore therapeutic strategies to overcome this resistance.
  • To elucidate the mechanistic link between EML4-ALK fusion and resistance to KRASG12C inhibition.

Main Methods:

  • Utilized preclinical models of KRASG12C-driven LUAD.
  • Analyzed acquired genomic alterations, specifically EML4-ALK fusion, in resistant tumors.
  • Evaluated the efficacy of combined ALK and KRASG12C inhibition.
  • Assessed the sensitivity of KRASG12C/EML4-ALK co-mutant cells to single-agent ALK inhibitors.
  • Investigated the downstream signaling pathways activated by EML4-ALK fusion.

Main Results:

  • Acquired EML4-ALK fusion was identified as a resistance mechanism to KRASG12C inhibitors in LUAD.
  • Combined inhibition of ALK and KRASG12C demonstrated significant therapeutic efficacy.
  • KRASG12C/EML4-ALK co-mutant cells showed sensitivity to ALK inhibitors, indicating potential for sequential therapy.
  • EML4-ALK fusion confers resistance by activating wild-type RAS signaling pathways.

Conclusions:

  • Combined ALK and KRASG12C inhibition is a promising therapeutic strategy for LUAD with acquired EML4-ALK fusion.
  • Sequential treatment with ALK inhibitors following KRASG12C inhibition may overcome resistance.
  • Targeting wild-type RAS activation downstream of EML4-ALK presents a novel therapeutic avenue.

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