1. Survival of pancreatic cancer cells lacking KRAS function.
- Author
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Muzumdar MD, Chen PY, Dorans KJ, Chung KM, Bhutkar A, Hong E, Noll EM, Sprick MR, Trumpp A, and Jacks T
- Subjects
- Animals, Benzimidazoles pharmacology, Carcinoma, Pancreatic Ductal genetics, Carcinoma, Pancreatic Ductal metabolism, DNA Copy Number Variations genetics, Humans, Immunoblotting, Indazoles pharmacology, Mice, Morpholines pharmacology, Pancreatic Neoplasms genetics, Phenylurea Compounds pharmacology, Piperidines pharmacology, Proto-Oncogene Mas, Proto-Oncogene Proteins p21(ras) genetics, Purines pharmacology, Pyrimidines pharmacology, Pyrimidinones pharmacology, Quinazolinones pharmacology, Sulfonamides pharmacology, Thiazoles pharmacology, Antineoplastic Agents pharmacology, Pancreatic Neoplasms metabolism, Proto-Oncogene Proteins p21(ras) metabolism
- 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.
- Published
- 2017
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