A role for the unfolded protein response stress sensor ERN1 in regulating the response to MEK inhibitors in KRAS mutant colon cancers

• Published in: Genome medicine Vol. 10; no. 1; pp. 90 - 13
• Main Authors: Šuštić, Tonći, van Wageningen, Sake, Bosdriesz, Evert, Reid, Robert J D, Dittmar, John, Lieftink, Cor, Beijersbergen, Roderick L, Wessels, Lodewyk F A, Rothstein, Rodney, Bernards, René
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 27.11.2018; BioMed Central; BMC
• Subjects: Antineoplastic Agents - pharmacology; Benzimidazoles - pharmacology; Cell Line, Tumor; Clinical trials; Colon cancer; Colonic Neoplasms - drug therapy; Colonic Neoplasms - genetics; Colorectal cancer; Colorectal carcinoma; CRISPR; Drug development; Endoplasmic reticulum; Endoplasmic Reticulum Stress; Endoribonucleases - genetics; Enzyme inhibitors; ERN1; Gene disruption; Gene expression; Gene mutations; Genetic aspects; Genetic screening; Genomes; HEK293 Cells; Humans; Immune response; Ire1; JNK; JUN; K-Ras protein; Kinases; MAP Kinase Kinase Kinases - antagonists & inhibitors; MAP Kinase Kinase Kinases - genetics; MEK inhibitor; MEK inhibitors; Mutation; Ploidy; Protein folding; Protein Kinase Inhibitors - pharmacology; Protein-Serine-Threonine Kinases - genetics; Proteins; Proto-Oncogene Proteins c-jun - genetics; Proto-Oncogene Proteins p21(ras) - genetics; Pyridones - pharmacology; Pyrimidinones - pharmacology; Sensors; Signal transduction; Stress (Physiology); TAK1 protein; Tumor cell lines; Tumor cells; Unfolded Protein Response; Yeast; Yeasts - genetics; ERN1; JUN; MEK inhibitor; Colon cancer; JNK; Ire1
• ISSN: 1756-994X; 1756-994X
• DOI: 10.1186/s13073-018-0600-z

Mutations in KRAS are frequent in human cancer, yet effective targeted therapeutics for these cancers are still lacking. Attempts to drug the MEK kinases downstream of KRAS have had limited success in clinical trials. Understanding the specific genomic vulnerabilities of KRAS-driven cancers may uncover novel patient-tailored treatment options. We first searched for synthetic lethal (SL) genetic interactions with mutant RAS in yeast with the ultimate aim to identify novel cancer-specific targets for therapy. Our method used selective ploidy ablation, which enables replication of cancer-specific gene expression changes in the yeast gene disruption library. Second, we used a genome-wide CRISPR/Cas9-based genetic screen in KRAS mutant human colon cancer cells to understand the mechanistic connection between the synthetic lethal interaction discovered in yeast and downstream RAS signaling in human cells. We identify loss of the endoplasmic reticulum (ER) stress sensor IRE1 as synthetic lethal with activated RAS mutants in yeast. In KRAS mutant colorectal cancer cell lines, genetic ablation of the human ortholog of IRE1, ERN1, does not affect growth but sensitizes to MEK inhibition. However, an ERN1 kinase inhibitor failed to show synergy with MEK inhibition, suggesting that a non-kinase function of ERN1 confers MEK inhibitor resistance. To investigate how ERN1 modulates MEK inhibitor responses, we performed genetic screens in ERN1 knockout KRAS mutant colon cancer cells to identify genes whose inactivation confers resistance to MEK inhibition. This genetic screen identified multiple negative regulators of JUN N-terminal kinase (JNK) /JUN signaling. Consistently, compounds targeting JNK/MAPK8 or TAK1/MAP3K7, which relay signals from ERN1 to JUN, display synergy with MEK inhibition. We identify the ERN1-JNK-JUN pathway as a novel regulator of MEK inhibitor response in KRAS mutant colon cancer. The notion that multiple signaling pathways can activate JUN may explain why KRAS mutant tumor cells are traditionally seen as highly refractory to MEK inhibitor therapy. Our findings emphasize the need for the development of new therapeutics targeting JUN activating kinases, TAK1 and JNK, to sensitize KRAS mutant cancer cells to MEK inhibitors.