TY - JOUR TI - Hyperactivation of ERK by multiple mechanisms is toxic to RTK-RAS mutation-driven lung adenocarcinoma cells AU - Unni, Arun M AU - Harbourne, Bryant AU - Oh, Min Hee AU - Wild, Sophia AU - Ferrarone, John R AU - Lockwood, William W AU - Varmus, Harold A2 - Cooper, Jonathan A VL - 7 PY - 2018 DA - 2018/11/26 SP - e33718 C1 - eLife 2018;7:e33718 DO - 10.7554/eLife.33718 UR - https://doi.org/10.7554/eLife.33718 AB - 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. KW - KRAS KW - EGFR KW - DUSP6 KW - mutual exclusivity KW - synthetic lethality KW - feedback inhibition JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -