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Differences in Signaling Patterns on PI3K Inhibition Reveal Context Specificity in KRAS-Mutant Cancers

Adam Stewart1, Elizabeth A Coker1,2, Sebastian Pölsterl1

  • 1Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom.

Molecular Cancer Therapeutics
|July 3, 2019
PubMed

Insights

Drug response varies across cancers with the same oncogene, like mutant KRAS (KRAS MT). Signaling pathway differences in colorectal cancer and non-small cell lung cancer impact targeted therapy effectiveness.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Drug response in cancers driven by the same oncogene (e.g., mutant KRAS) can differ significantly.
  • These differences may stem from distinct signal transduction pathway rewiring specific to cancer types.

Purpose of the Study:

  • To investigate dynamic signaling alterations in mutant KRAS (KRAS MT) non-small cell lung cancer (NSCLC), colorectal cancer, and pancreatic ductal adenocarcinoma (PDAC) cells.
  • To identify differences in cellular signaling responses to targeted anticancer drugs across these KRAS MT cancer types.

Main Methods:

  • Utilized an antibody-based phosphoproteomic platform to analyze 50 phosphoproteins.
  • Examined responses to seven targeted anticancer drugs in 30 KRAS MT cell lines and patient-derived cancer cells.
  • Assessed signaling changes upon exposure to the pan-PI3K inhibitor pictilisib.

Main Results:

  • Observed significant differences in dynamic signaling between colorectal cancer and NSCLC cell lines treated with pictilisib.
  • Noted a lack of p-AKTser473 reduction in colorectal cancer cells (P = 0.037).
  • Identified a lack of compensatory p-MEK increase in NSCLC cells (P = 0.036).

Conclusions:

  • Demonstrated that distinct signal transduction rewiring exists between different tumor types harboring KRAS MT.
  • These pathway differences influence the efficacy of targeted therapy combinations.

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