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Survival of pancreatic cancer cells lacking KRAS function
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Journal Article
Survival of pancreatic cancer cells lacking KRAS function
2017
Overview
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.
Pancreatic cancer cells may develop resistance to KRAS inhibitors due to activation of compensatory pathways. In this study, the authors demonstrate that KRAS is dispensable in a subset of pancreatic cancer and that PI3K signalling may have an important role in mediating tumor growth following KRAS inhibition.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
1-Phosphatidylinositol 3-kinase
/ Animals
/ Antineoplastic Agents - pharmacology
/ Benzimidazoles - pharmacology
/ Cancer
/ Carcinoma, Pancreatic Ductal - genetics
/ Carcinoma, Pancreatic Ductal - metabolism
/ CRISPR
/ DNA Copy Number Variations - genetics
/ Genomes
/ Humanities and Social Sciences
/ Humans
/ Kinases
/ Mice
/ Mutation
/ Pancreatic Neoplasms - genetics
/ Pancreatic Neoplasms - metabolism
/ Phenylurea Compounds - pharmacology
/ Proto-Oncogene Proteins p21(ras) - genetics
/ Proto-Oncogene Proteins p21(ras) - metabolism
/ Pyrimidinones - pharmacology
/ Quinazolinones - pharmacology
/ Science
