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Survival of pancreatic cancer cells lacking KRAS function

Author(s)
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.; ... Show more Show less
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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.
Date issued
2017-10
URI
http://hdl.handle.net/1721.1/112693
Department
Massachusetts Institute of Technology. Department of Biology; Koch Institute for Integrative Cancer Research at MIT
Journal
Nature Communications
Publisher
Nature Publishing Group
Citation
Muzumdar, Mandar Deepak et al. “Survival of Pancreatic Cancer Cells Lacking KRAS Function.” Nature Communications 8, 1 (October 2017): 1090 © 2017 The Author(s)
Version: Final published version
ISSN
2041-1723

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