A role for the unfolded protein response stress sensor ERN1 in regulating the response to MEK inhibitors in KRAS mutant colon cancers
| Autor: | Lodewyk F. A. Wessels, René Bernards, Robert J.D. Reid, John C. Dittmar, Evert Bosdriesz, Cor Lieftink, Roderick L. Beijersbergen, Sake van Wageningen, Rodney Rothstein, Tonći Šuštić |
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| Přispěvatelé: | Bioinformatics |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Yeasts/genetics Proto-Oncogene Proteins c-jun Mutant lcsh:Medicine medicine.disease_cause Colonic Neoplasms/drug therapy Yeasts Genetics (clinical) Tumor Benzimidazoles/pharmacology Pyrimidinones/pharmacology Kinase MEK inhibitor MAP Kinase Kinase Kinases Endoplasmic Reticulum Stress 3. Good health Colon cancer Colonic Neoplasms Molecular Medicine KRAS Signal transduction Antineoplastic Agents/pharmacology lcsh:QH426-470 Pyridones Protein-Serine-Threonine Kinases/genetics Antineoplastic Agents Pyrimidinones Ire1 Biology Protein Serine-Threonine Kinases Cell Line Proto-Oncogene Proteins p21(ras) Proto-Oncogene Proteins p21(ras)/genetics 03 medical and health sciences SDG 3 - Good Health and Well-being Cell Line Tumor Endoribonucleases Endoribonucleases/genetics Genetics medicine Humans Molecular Biology Protein Kinase Inhibitors JUN Pyridones/pharmacology Research lcsh:R Correction ERN1 Proto-Oncogene Proteins c-jun/genetics lcsh:Genetics MAP Kinase Kinase Kinases/antagonists & inhibitors 030104 developmental biology HEK293 Cells Protein Kinase Inhibitors/pharmacology Cancer cell Cancer research Unfolded protein response Unfolded Protein Response Benzimidazoles JNK Genetic screen |
| Zdroj: | Genome Medicine Šuštić, T, van Wageningen, S, Bosdriesz, E, Reid, R J D, Dittmar, J, Lieftink, C, Beijersbergen, R L, Wessels, L F A, Rothstein, R & Bernards, R 2018, ' A role for the unfolded protein response stress sensor ERN1 in regulating the response to MEK inhibitors in KRAS mutant colon cancers ', Genome Medicine, vol. 10, no. 1, 90, pp. 90 . https://doi.org/10.1186/s13073-018-0600-z Genome Medicine, 10(1):90. BioMed Central Genome Medicine, Vol 10, Iss 1, Pp 1-13 (2018) |
| ISSN: | 1756-994X |
| Popis: | BackgroundMutations inKRASare 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 ofKRAS-driven cancers may uncover novel patient-tailored treatment options.MethodsWe first searched for synthetic lethal (SL) genetic interactions with mutantRASin 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 inKRASmutant human colon cancer cells to understand the mechanistic connection between the synthetic lethal interaction discovered in yeast and downstream RAS signaling in human cells.ResultsWe identify loss of the endoplasmic reticulum (ER) stress sensorIRE1as synthetic lethal with activatedRASmutants in yeast. InKRASmutant colorectal cancer cell lines, genetic ablation of the human ortholog ofIRE1,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 inERN1knockoutKRASmutant 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.ConclusionsWe identify the ERN1-JNK-JUN pathway as a novel regulator of MEK inhibitor response inKRASmutant colon cancer. The notion that multiple signaling pathways can activate JUN may explain whyKRASmutant 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 sensitizeKRASmutant cancer cells to MEK inhibitors. |
| Databáze: | OpenAIRE |
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