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Updated: Jun 13, 2026

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Oncogenic K-ras activates p38 to maintain colorectal cancer cell proliferation during MEK inhibition

Winan J van Houdt1, Menno T de Bruijn, Benjamin L Emmink

  • 1Department of Surgery, University Medical Center Utrecht, Heidelberglaan, Utrecht, The Netherlands.

Cellular Oncology : the Official Journal of the International Society for Cellular Oncology
|April 24, 2010
PubMed
Abstract

Insights

Oncogenic K-ras activates p38alpha, promoting colorectal tumor cell proliferation during MEK/ERK pathway inhibition. Targeting p38alpha may overcome resistance to MEK-targeted therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Signaling Pathways

Background:

  • Activating mutations in K-ras are common in colon carcinomas.
  • K-ras is a challenging drug target, leading to focus on the MEK/ERK pathway.
  • This study investigates K-ras's influence on colorectal tumor cell dependence on MEK/ERK signaling.

Purpose of the Study:

  • To determine if endogenous oncogenic K-ras impacts colorectal tumor cell reliance on MEK/ERK signaling.
  • To explore the role of the p38 pathway in mediating resistance to MEK/ERK inhibition in K-ras-mutant colorectal cancers.

Main Methods:

  • Utilized K-ras mutant colorectal tumor cell lines (C26, HCT116, L169).
  • Employed RNA interference (RNAi) to suppress K-ras, MEK/ERK, and p38 pathways.
  • Inhibited MEK with U0126 and p38 with SB203850.

Main Results:

  • MEK inhibition initially reduced proliferation but cells recovered within two weeks.
  • K-ras-suppressed cells treated with ERK inhibition entered senescence.
  • MEK or ERK inhibition activated p38alpha in a K-ras-dependent manner.
  • p38alpha inhibition prevented tumor cell recovery during prolonged MEK inhibition.

Conclusions:

  • Oncogenic K-ras activates p38alpha to sustain proliferation under MEK inhibition.
  • MEK-targeting therapies may induce a dependency on p38alpha in colorectal tumors.
  • Understanding this crosstalk is crucial for developing effective cancer treatments.

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