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Molecular determinants of response to PI3K/akt/mTOR and KRAS pathways inhibitors in NSCLC cell lines

Alice Iezzi1, Elisa Caiola1, Marika Colombo1

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

American Journal of Cancer Research
|January 8, 2021
PubMed

Insights

Targeting cancer pathways PI3K/akt/mTOR and KRAS/MEK/ERK shows limited clinical success. This study suggests p53 mutational status, not pathway alterations, may predict response to PI3K inhibitors in non-small cell lung cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Targeted therapies for PI3K/akt/mTOR and KRAS/MEK/ERK pathways show limited clinical efficacy in cancer.
  • A lack of clear molecular predictors contributes to the clinical failure of these targeted agents.

Purpose of the Study:

  • To evaluate the cytotoxic activity of inhibitors targeting PI3K/akt/mTOR and KRAS/MEK/ERK pathways.
  • To identify molecular determinants of response to these inhibitors in non-small cell lung cancer (NSCLC) cell lines.

Main Methods:

  • Assessed cytotoxic activity of pathway inhibitors across ten NSCLC cell lines with PI3K, KRAS, or both alterations.
  • Performed molecular analyses to evaluate target modulation post-treatment.
  • Correlated drug sensitivity with specific genetic alterations and p53 mutational status.

Main Results:

  • No significant correlation found between KRAS/PI3K mutations and sensitivity to pathway inhibitors.
  • PI3K/akt/mTOR and KRAS/MEK/ERK pathway alterations alone are insufficient to guide treatment selection.
  • p53 mutational status emerged as a key factor differentiating sensitivity to PI3K pathway inhibitors.

Conclusions:

  • p53 status is a potential biomarker for predicting response to PI3K pathway inhibitors in NSCLC.
  • Current understanding of PI3K/akt/mTOR and KRAS/MEK/ERK pathway alterations is insufficient for precise treatment selection.
  • Further research into biomarkers like p53 is crucial for improving targeted cancer therapy efficacy.
Keywords:
Non-small cell lung cancerPI3K inhibitorsmTOR inhibitorsp53

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