Oncogenic KRAS sensitizes premalignant, but not malignant cells, to Noxa-dependent apoptosis through the activation of the MEK/ERK pathway

Annalisa Conti, Maria Teresa Majorini, Richard Elliott, Alan Ashworth, Christopher J Lord, Carlotta Cancelliere, Alberto Bardelli, Pierfausto Seneci, Henning Walczak, Domenico Delia, Daniele Lecis

Research output: Contribution to journalArticlepeer-review

Abstract

KRAS is mutated in about 20-25% of all human cancers and especially in pancreatic, lung and colorectal tumors. Oncogenic KRAS stimulates several pro-survival pathways, but it also triggers the trans-activation of pro-apoptotic genes. In our work, we show that G13D mutations of KRAS activate the MAPK pathway, and ERK2, but not ERK1, up-regulates Noxa basal levels. Accordingly, premalignant epithelial cells are sensitized to various cytotoxic compounds in a Noxa-dependent manner. In contrast to these findings, colorectal cancer cell sensitivity to treatment is independent of KRAS status and Noxa levels are not up-regulated in the presence of mutated KRAS despite the fact that ERK2 still promotes Noxa expression. We therefore speculated that other survival pathways are counteracting the pro-apoptotic effect of mutated KRAS and found that the inhibition of AKT restores sensitivity to treatment, especially in presence of oncogenic KRAS. In conclusion, our work suggests that the pharmacological inhibition of the pathways triggered by mutated KRAS could also switch off its oncogene-activated pro-apoptotic stimulation. On the contrary, the combination of chemotherapy to inhibitors of specific pro-survival pathways, such as the one controlled by AKT, could enhance treatment efficacy by exploiting the pro-death stimulation derived by oncogene activation.

Original languageEnglish
Pages (from-to)10994-1008
Number of pages15
JournalOncotarget
Volume6
Issue number13
DOIs
Publication statusPublished - 10 May 2015

Keywords

  • Antineoplastic Agents/pharmacology
  • Apoptosis/drug effects
  • Blotting, Western
  • Cell Proliferation/drug effects
  • Cells, Cultured
  • Colorectal Neoplasms/drug therapy
  • Flow Cytometry
  • High-Throughput Screening Assays
  • Humans
  • MAP Kinase Signaling System/drug effects
  • Mammary Glands, Human/cytology
  • Mutation/genetics
  • Phosphorylation/drug effects
  • Proto-Oncogene Proteins c-bcl-2/metabolism
  • Proto-Oncogene Proteins p21(ras)/genetics

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