Hyperactivation of ERK by multiple mechanisms is toxic to RTK-RAS mutation-driven lung adenocarcinoma cells

eLife

Harold Varmus¹  William W Lockwood²  Bryant Harbourne²  Sophia Wild²  Min Hee Oh²  John R Ferrarone³  Arun M Unni³ 

[1] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada;Department of Integrative Oncology, British Columbia Cancer Agency, Vancouver, Canada;Meyer Cancer Center, Weill Cornell Medicine, New York, United States;

关键词: KRAS;    EGFR;    DUSP6;    mutual exclusivity;    synthetic lethality;    feedback inhibition;   

DOI  :  10.7554/eLife.33718

来源: DOAJ

【 摘 要 】

Synthetic lethality results when mutant KRAS and EGFR proteins are co-expressed in human lung adenocarcinoma (LUAD) cells, revealing the biological basis for mutual exclusivity of KRAS and EGFR mutations. We have now defined the biochemical events responsible for the toxic effects by combining pharmacological and genetic approaches and to show that signaling through extracellular signal-regulated kinases (ERK1/2) mediates the toxicity. These findings imply that tumors with mutant oncogenes in the RAS pathway must restrain the activity of ERK1/2 to avoid toxicities and enable tumor growth. A dual specificity phosphatase, DUSP6, that negatively regulates phosphorylation of (P)-ERK is up-regulated in EGFR- or KRAS-mutant LUAD, potentially protecting cells with mutations in the RAS signaling pathway, a proposal supported by experiments with DUSP6-specific siRNA and an inhibitory drug. Targeting DUSP6 or other negative regulators might offer a treatment strategy for certain cancers by inducing the toxic effects of RAS-mediated signaling.

【 授权许可】

Unknown