Hyperactivation of extracellular signal-regulated kinase (ERK) by RAS-mediated signaling or inhibition of dual specificity phosphatase 6 (DUSP6) is associated with toxicity in lung adenocarcinoma cells with mutations in KRAS or EGFR

Abstract

We recently described the synthetic lethality that results when mutant KRAS and mutant EGFR are coexpressed in human lung adenocarcinoma (LUAD) cells, revealing the biological basis for the mutual exclusivity of KRAS and EGFR mutations in lung cancers. We have now further defined the biochemical events responsible for the toxic effects of signaling through the RAS pathway. By combining pharmacological and genetic approaches, we have developed multiple lines of evidence that signaling through extracellular signal-regulated kinases (ERK1/2) mediates the toxicity. These findings imply that tumors with mutant oncogenes that drive signaling through the RAS pathway must restrain the activity of ERK1/2 to avoid cell toxicities and enable tumor growth. In particular, a dual specificity phosphatase, DUSP6, regulates phosphorylated (P)-ERK levels in lung adenocarcinoma cells, providing negative feedback to the RAS signaling pathway. Accordingly, inhibition of DUSP6 is cytotoxic in LUAD cells driven by either mutant KRAS or mutant EGFR, phenocopying the effects of co-expression of mutant KRAS and EGFR. Together, these data suggest that targeting DUSP6 or other feedback regulators of the EGFR-KRAS-ERK pathway may offer a strategy for treating certain cancers by exceeding an upper threshold of RAS-mediated signaling.