Hyperactivation of ERK by multiple mechanisms is toxic to RTK-RAS mutation-driven lung adenocarcinoma cells
- Weill Cornell Medicine, United States
- British Columbia Cancer Agency, Canada
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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 2 and Figure 2-supplemental figure 1 in the Methods section and/or in the text.
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Expression profiling of 83 matched pairs of lung adenocarcinomas and non-malignant adjacent tissueNCBI Gene Expression Omnibus, GSE75037.
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Oncogene Signature DatasetNCBI Gene Expression Omnibus, GSE3151.
Article and author information
Author details
Funding
Cancer Research Society
- William W Lockwood
National Institutes of Health
- Harold Varmus
Meyer Cancer Center
- Harold Varmus
Terry Fox Research Institute
- William W Lockwood
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Jonathan A. Cooper, Fred Hutchinson Cancer Research Center, United States
Version history
- Received: November 21, 2017
- Accepted: November 26, 2018
- Accepted Manuscript published: November 26, 2018 (version 1)
- Version of Record published: December 18, 2018 (version 2)
Copyright
© 2018, Unni et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Hyperactivation of ERK by multiple mechanisms is toxic to RTK-RAS mutation-driven lung adenocarcinoma cells
eLife 7:e33718.
https://doi.org/10.7554/eLife.33718
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