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Different metabolic responses to PI3K inhibition in NSCLC cells harboring wild-type and G12C mutant KRAS

Elisa Caiola1, Laura Brunelli2, Mirko Marabese1

  • 1Laboratory of Molecular Pharmacology, Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.

Oncotarget
|June 11, 2016
PubMed

Insights

KRAS mutations in non-small-cell lung cancer impact treatment response. PI3K/AKT/mTOR inhibitors affect cancer cell metabolism differently based on KRAS status, suggesting targeted therapy potential.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Metabolism

Background:

  • KRAS mutations in non-small-cell lung cancer (NSCLC) are linked to poor treatment outcomes.
  • The PI3K/AKT/mTOR pathway is frequently activated in cancers and is a target for therapy.
  • Both KRAS and PI3K/AKT/mTOR signaling influence cancer cell metabolism.

Purpose of the Study:

  • To investigate the metabolic effects of PI3K/AKT/mTOR inhibitors (BEZ235, BKM120) in NSCLC cells with different KRAS mutation statuses.
  • To determine if metabolic responses to PI3K inhibition differ between wild-type (WT) and mutated KRAS NSCLC cells.
  • To explore potential therapeutic strategies based on differential metabolic vulnerabilities.

Main Methods:

  • Utilized isogenic NSCLC cell clones with wild-type (WT) and KRAS G12C mutations.
  • Administered PI3K/AKT/mTOR inhibitors BEZ235 and BKM120.
  • Performed metabolomics analysis to assess metabolic alterations.

Main Results:

  • PI3K inhibition impaired glutamine metabolism in KRAS-G12C cells and serine metabolism in KRAS-WT cells.
  • While cell growth and apoptosis markers were similar, PI3K inhibitors induced autophagy in KRAS-WT but not KRAS-G12C cells.
  • KRAS-G12C cells showed a significant reduction in ammonia production, linked to altered glutamine metabolism.

Conclusions:

  • Distinct metabolic responses to PI3K/AKT/mTOR inhibitors exist between WT and KRAS-mutated NSCLC cells.
  • These metabolic differences, particularly in glutamine and serine pathways, could be exploited for targeted therapies.
  • Findings support developing combination treatments that leverage the metabolic vulnerabilities of KRAS-mutated NSCLC.
Keywords:
BEZ235BKM120KRASNSCLCmetabolomics

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