In vivo oncogenic conflict triggered by co-existing KRAS and EGFR activating mutations in lung adenocarcinoma

Abstract

Activating mutations in KRAS and EGFR, the two most frequent oncogenes in human lung adenocarcinoma, are mutually exclusive, a phenotype attributed to functional redundancy implying lack of positive selection. Employing a mouse model expressing EGFRL858R in advanced KrasG12V-driven tumors we show that their mutual exclusivity can be explained by detrimental effects of their co-expression in lung adenocarcinoma. In vivo, expression of EGFRL858R in KrasG12V-driven tumors triggers replicative stress and apoptosis, while the surviving cells enter a transient cytostatic state incompatible with tumor development that is fully reversible upon discontinued EGFRL858R expression. Eventually, sustained expression of both mutants induces attenuation of oncogenic signaling to levels compatible with proliferation and tumor growth resulting in high sensitivity to Mek inhibition. Our results indicate that the mutual exclusivity of KRAS and EGFR mutations occurs as a combination of cellular toxicity and signal adjustment resulting in lack of selective advantage for cells expressing both oncogenes.

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Acknowledgements

We thank J. Haigh for providing Rosa26-LSLrtTA mice. This work was supported by the European Research Council (ERC-AG/ 250297-RAS AEAD), EU-Framework Programme (HEALTH-F2-2010-259770/LUNGTARGET and HEALTH-2010-260791/EUROCANPLATFORM), Spanish Ministry of Economy and Competitiveness (SAF2011-30173) and Autonomous Community of Madrid (S2011/BDM-2470/ONCOCYCLE) to MB. CA is the recipient of a postdoctoral fellowship from the Spanish Association Against Cancer (AECC). We thank A. Ventura, O. Segatto and T. Cash for critical reading of the manuscript and S. Antón for constructive discussion.

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Correspondence to C Ambrogio or D Santamaría.

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Ambrogio, C., Barbacid, M. & Santamaría, D. In vivo oncogenic conflict triggered by co-existing KRAS and EGFR activating mutations in lung adenocarcinoma. Oncogene 36, 2309–2318 (2017). https://doi.org/10.1038/onc.2016.385

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