Survival of pancreatic cancer cells lacking KRAS function

Mandar Deepak Muzumdar, Pan-Yu Chen, Kimberly Judith Dorans, Katherine Minjee Chung, Arjun Bhutkar, Erin Hong, Elisa M. Noll, Martin R. Sprick, Andreas Trumpp and Tyler Jacks ()
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Mandar Deepak Muzumdar: Massachusetts Institute of Technology
Pan-Yu Chen: Massachusetts Institute of Technology
Kimberly Judith Dorans: Massachusetts Institute of Technology
Katherine Minjee Chung: Massachusetts Institute of Technology
Arjun Bhutkar: Massachusetts Institute of Technology
Erin Hong: Massachusetts Institute of Technology
Elisa M. Noll: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM)
Martin R. Sprick: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM)
Andreas Trumpp: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM)
Tyler Jacks: Massachusetts Institute of Technology

Nature Communications, 2017, vol. 8, issue 1, 1-19

Abstract: 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: 2017
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DOI: 10.1038/s41467-017-00942-5

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