Survival of pancreatic cancer cells lacking KRAS function
Activating mutations in the proto-oncogene KRAS are a hallmark of pancreatic ductal adenocarcinoma (PDAC), an aggressive malignancy with few effective therapeutic options. Despite efforts to develop KRAS-targeted drugs, the absolute dependence of PDAC cells on KRAS remains incompletely understood. H...
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| Format: | Article |
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Nature Publishing Group
2017
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| Online Access: | http://hdl.handle.net/1721.1/112693 https://orcid.org/0000-0002-4450-7570 https://orcid.org/0000-0001-9119-8718 https://orcid.org/0000-0001-5785-8911 |
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| author | Noll, Elisa M. Sprick, Martin R. Trumpp, Andreas Muzumdar, Mandar Chen, Pan-Yu Dorans, Kimberly Chung, Katherine Minjee Bhutkar, Arjun Hong, Erin Jacks, Tyler E. |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Noll, Elisa M. Sprick, Martin R. Trumpp, Andreas Muzumdar, Mandar Chen, Pan-Yu Dorans, Kimberly Chung, Katherine Minjee Bhutkar, Arjun Hong, Erin Jacks, Tyler E. |
| author_sort | Noll, Elisa M. |
| collection | MIT |
| description | Activating mutations in the proto-oncogene KRAS are a hallmark of pancreatic ductal adenocarcinoma (PDAC), an aggressive malignancy with few effective therapeutic options. Despite efforts to develop KRAS-targeted drugs, the absolute dependence of PDAC cells on KRAS remains incompletely understood. Here we model complete KRAS inhibition using CRISPR/Cas-mediated genome editing and demonstrate that KRAS is dispensable in a subset of human and mouse PDAC cells. Remarkably, nearly all KRAS deficient cells exhibit phosphoinositide 3-kinase (PI3K)-dependent mitogen-activated protein kinase (MAPK) signaling and induced sensitivity to PI3K inhibitors. Furthermore, comparison of gene expression profiles of PDAC cells retaining or lacking KRAS reveal a role of KRAS in the suppression of metastasis-related genes. Collectively, these data underscore the potential for PDAC resistance to even the very best KRAS inhibitors and provide insights into mechanisms of response and resistance to KRAS inhibition. |
| first_indexed | 2024-09-23T15:19:01Z |
| format | Article |
| id | mit-1721.1/112693 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T15:19:01Z |
| publishDate | 2017 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | mit-1721.1/1126932022-09-29T14:11:22Z Survival of pancreatic cancer cells lacking KRAS function Noll, Elisa M. Sprick, Martin R. Trumpp, Andreas Muzumdar, Mandar Chen, Pan-Yu Dorans, Kimberly Chung, Katherine Minjee Bhutkar, Arjun Hong, Erin Jacks, Tyler E. Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT Muzumdar, Mandar Chen, Pan-Yu Dorans, Kimberly Chung, Katherine Minjee Bhutkar, Arjun Hong, Erin Jacks, Tyler E. Activating mutations in the proto-oncogene KRAS are a hallmark of pancreatic ductal adenocarcinoma (PDAC), an aggressive malignancy with few effective therapeutic options. Despite efforts to develop KRAS-targeted drugs, the absolute dependence of PDAC cells on KRAS remains incompletely understood. Here we model complete KRAS inhibition using CRISPR/Cas-mediated genome editing and demonstrate that KRAS is dispensable in a subset of human and mouse PDAC cells. Remarkably, nearly all KRAS deficient cells exhibit phosphoinositide 3-kinase (PI3K)-dependent mitogen-activated protein kinase (MAPK) signaling and induced sensitivity to PI3K inhibitors. Furthermore, comparison of gene expression profiles of PDAC cells retaining or lacking KRAS reveal a role of KRAS in the suppression of metastasis-related genes. Collectively, these data underscore the potential for PDAC resistance to even the very best KRAS inhibitors and provide insights into mechanisms of response and resistance to KRAS inhibition. 2017-12-11T19:48:01Z 2017-12-11T19:48:01Z 2017-10 2017-06 2017-12-11T18:31:16Z Article http://purl.org/eprint/type/JournalArticle 2041-1723 http://hdl.handle.net/1721.1/112693 Muzumdar, Mandar Deepak et al. “Survival of Pancreatic Cancer Cells Lacking KRAS Function.” Nature Communications 8, 1 (October 2017): 1090 © 2017 The Author(s) https://orcid.org/0000-0002-4450-7570 https://orcid.org/0000-0001-9119-8718 https://orcid.org/0000-0001-5785-8911 http://dx.doi.org/10.1038/s41467-017-00942-5 Nature Communications Creative Commons Attribution 4.0 International https://creativecommons.org/licenses/by/4.0/ application/pdf Nature Publishing Group Nature |
| spellingShingle | Noll, Elisa M. Sprick, Martin R. Trumpp, Andreas Muzumdar, Mandar Chen, Pan-Yu Dorans, Kimberly Chung, Katherine Minjee Bhutkar, Arjun Hong, Erin Jacks, Tyler E. Survival of pancreatic cancer cells lacking KRAS function |
| title | Survival of pancreatic cancer cells lacking KRAS function |
| title_full | Survival of pancreatic cancer cells lacking KRAS function |
| title_fullStr | Survival of pancreatic cancer cells lacking KRAS function |
| title_full_unstemmed | Survival of pancreatic cancer cells lacking KRAS function |
| title_short | Survival of pancreatic cancer cells lacking KRAS function |
| title_sort | survival of pancreatic cancer cells lacking kras function |
| url | http://hdl.handle.net/1721.1/112693 https://orcid.org/0000-0002-4450-7570 https://orcid.org/0000-0001-9119-8718 https://orcid.org/0000-0001-5785-8911 |
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