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

Arun M Unni,John R Ferrarone,Sophia Wild,William W Lockwood,Min Hee Oh,Bryant Harbourne,Harold Varmus

doi:10.7554/elife.33718

Arun M Unni, John R Ferrarone + Show 5 more

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https://doi.org/10.7554/elife.33718

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Abstract

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.

Highlights

Extensive characterization of cancer genomes has begun to change the classification of neoplasms and the choice of therapies (Garraway and Lander, 2013)
We recently reported that the mutual exclusivity of gain-of-function mutations of EGFR and KRAS, two proto-oncogenes often individually mutated in lung adenocarcinomas (LUADs), can be explained by such synthetic toxicity, despite the fact that products of these two genes operate in overlapping signaling pathways and might have been mutually exclusive because of functional redundancies (Unni et al, 2015)
Synthetic lethality induced by co-expression of mutant KRAS and EGFR is mediated through increased ERK signaling

Summary

Introduction

Extensive characterization of cancer genomes has begun to change the classification of neoplasms and the choice of therapies (Garraway and Lander, 2013). Cancers continue to accumulate mutations during carcinogenesis, producing tumor subclones with selectable features such as drug resistance or enhanced growth potential (McGranahan and Swanton, 2017). Despite this heterogeneity, consistent patterns have been observed, such as the high frequency of gain-of-function or loss-of-function mutations affecting specific proto-oncogenes or tumor suppressor genes in cancers that arise in certain cell lineages. Examples of these ‘mutually exclusive’ pairs of mutations have been reported in a variety of cancers (Yoshida et al, 2011; Unni et al, 2015; Petti et al, 2006; Sensi et al, 2006; Varmus et al, 2016); the mutual exclusivity has usually been attributed either to a loss of a selective advantage of a mutation in one gene after a change in the other has occurred (‘functional redundancy’) or to the toxicity (including ‘synthetic lethality’) conferred by the coexistence of both mutations in the same cells

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