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The synergistic interaction of MEK and PI3K inhibitors is modulated by mTOR inhibition

E J Haagensen1, S Kyle, G S Beale

  • 1Drug Discovery and Imaging, Newcastle Cancer Centre, Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle-upon-Tyne, UK.

British Journal of Cancer
|March 15, 2012
PubMed
Abstract

Insights

Targeting both PI3K and MEK pathways shows synergistic cancer growth inhibition. Specific PI3K inhibitors combined with MEK inhibitors yield greater synergy than dual PI3K/mTOR inhibitors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Combined targeting of MAPK and PI3K signaling pathways is crucial for optimal cancer therapy.
  • This study investigates MEK inhibitors (AZD6244, PD0325901) with PI3K inhibitors (NVP-BEZ235, GDC-0941) in colorectal cancer cells.

Purpose of the Study:

  • To evaluate the synergistic effects of combined MEK and PI3K pathway inhibition in colorectal cancer.
  • To compare the efficacy of specific PI3K inhibitors versus dual PI3K/mTOR inhibitors when combined with MEK inhibitors.

Main Methods:

  • Utilized Sulforhodamine B assay, clonogenicity, and western blotting to assess growth inhibition, survival, and signal transduction.
  • Tested combinations in HCT116, HT29, and DLD1 colorectal cancer cell lines.

Main Results:

  • All MEK/PI3K inhibitor combinations demonstrated significant synergistic growth inhibition.
  • GDC-0941 showed greater synergy with MEK inhibitors compared to NVP-BEZ235.
  • NVP-BEZ235's reduced synergy may stem from mTOR inhibition; adding an mTOR inhibitor further compromised synergy.

Conclusions:

  • Dual targeting of PI3K and MEK pathways effectively induces synergistic growth inhibition in colorectal cancer.
  • Specific PI3K inhibitors, when combined with MEK inhibitors, offer superior synergy over dual PI3K/mTOR inhibitors.

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