Survival of pancreatic cancer cells lacking KRAS function
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Author
Muzumdar, Mandar Deepak
Chen, Pan-Yu
Dorans, Kimberly Judith
Chung, Katherine Minjee
Bhutkar, Arjun
Hong, Erin
Noll, Elisa M.
Sprick, Martin R.
Trumpp, Andreas
Jacks, Tyler
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https://doi.org/10.1038/s41467-017-00942-5Metadata
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Muzumdar, Mandar Deepak, Pan-Yu Chen, Kimberly Judith Dorans, Katherine Minjee Chung, Arjun Bhutkar, Erin Hong, Elisa M. Noll, Martin R. Sprick, Andreas Trumpp, and Tyler Jacks. 2017. “Survival of pancreatic cancer cells lacking KRAS function.” Nature Communications 8 (1): 1090. doi:10.1038/s41467-017-00942-5. http://dx.doi.org/10.1038/s41467-017-00942-5.Abstract
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.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5653666/pdf/Terms of Use
This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAACitable link to this page
http://nrs.harvard.edu/urn-3:HUL.InstRepos:34492255
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