A CRISPR screen identifies MAPK7 as a target for combination with MEK inhibition in KRAS mutant NSCLC
| العنوان: | A CRISPR screen identifies MAPK7 as a target for combination with MEK inhibition in KRAS mutant NSCLC |
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| المؤلفون: | Nicholas Dompe, David Stokoe, Katherine R. Welker Leng, Trinna L. Cuellar, Marie Evangelista, Sara A. Watson, Benjamin Haley, Christiaan Klijn, Colin K. Watanabe, Richard M. Neve, Jenna Port |
| المصدر: | PLoS ONE PLoS ONE, Vol 13, Iss 6, p e0199264 (2018) |
| بيانات النشر: | Public Library of Science, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, MAPK/ERK pathway, Genetic Screens, Cell signaling, Mutant, MAPK7, Cancer Treatment, Gene Identification and Analysis, lcsh:Medicine, Signal transduction, ERK signaling cascade, medicine.disease_cause, Synthetic Genome Editing, Genome Engineering, Lung and Intrathoracic Tumors, chemistry.chemical_compound, Mice, Genomic Library Screening, Carcinoma, Non-Small-Cell Lung, Medicine and Health Sciences, Clustered Regularly Interspaced Short Palindromic Repeats, lcsh:Science, Gene knockdown, Multidisciplinary, MEK inhibitor, Crispr, Signaling cascades, Oncology, Engineering and Technology, Synthetic Biology, KRAS, Research Article, Biotechnology, Cell biology, MAPK signaling cascades, MAP Kinase Signaling System, Bioengineering, Library Screening, Biology, Research and Analysis Methods, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, medicine, Genetics, Biomarkers, Tumor, Animals, Humans, Molecular Biology Techniques, neoplasms, Molecular Biology, Mitogen-Activated Protein Kinase 7, Cobimetinib, Molecular Biology Assays and Analysis Techniques, lcsh:R, Biology and Life Sciences, Cancers and Neoplasms, Synthetic Genomics, Xenograft Model Antitumor Assays, respiratory tract diseases, Non-Small Cell Lung Cancer, 030104 developmental biology, chemistry, Synthetic Bioengineering, A549 Cells, Cancer research, lcsh:Q, Genetic screen |
| الوصف: | Mutant KRAS represents one of the most frequently observed oncogenes in NSCLC, yet no therapies are approved for tumors that express activated KRAS variants. While there is strong rationale for the use of MEK inhibitors to treat tumors with activated RAS/MAPK signaling, these have proven ineffective clinically. We therefore implemented a CRISPR screening approach to identify novel agents to sensitize KRAS mutant NSCLC cells to MEK inhibitor treatment. This approach identified multiple components of the canonical RAS/MAPK pathway consistent with previous studies. In addition, we identified MAPK7 as a novel, strong hit and validated this finding using multiple orthogonal approaches including knockdown and pharmacological inhibition. We show that MAPK7 inhibition attenuates the re-activation of MAPK signaling occurring following long-term MEK inhibition, thereby illustrating that MAPK7 mediates pathway reactivation in the face of MEK inhibition. Finally, genetic knockdown of MAPK7 combined with the MEK inhibitor cobimetinib in a mutant KRAS NSCLC xenograft model to mediate improved tumor growth inhibition. These data highlight that MAPK7 represents a promising target for combination treatment with MEK inhibition in KRAS mutant NSCLC. |
| اللغة: | English |
| تدمد: | 1932-6203 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::89538d3aaf695f323094e1b37a70487a http://europepmc.org/articles/PMC6005515 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....89538d3aaf695f323094e1b37a70487a |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19326203 |
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