Transcriptomics,Genomics

Dataset Information

27

Survival of pancreatic cancer cells lacking KRAS function


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 modeled complete KRAS inhibition using CRISPR/Cas-mediated genome editing. While KRAS knockout led to decreased in vitro proliferation and impaired in vivo tumorigenic growth, KRAS was dispensable in a subset of human and mouse PDAC cells. KRAS knockout cells exhibited hyperactivation of the PI3K pathway and induced sensitivity to phosphoinositide 3-kinase (PI3K) inhibitors. Mechanistically, PI3K inhibition in KRAS knockout cells led to transient mitogen-activated protein kinase (MAPK) blockade while impeding AKT-dependent 4EBP1 phosphorylation and cap-dependent translation. Furthermore, comparison of gene expression profiles of cells retaining or lacking KRAS revealed a novel functional role of KRAS in the suppression of metastasis-related genes. Accordingly, KRAS knockout gene expression signatures correlated with PDAC circulating tumor cell (CTC) signatures, and human PDAC tumors with gene expression patterns enriched in signatures from KRAS knockout cells were associated with worse survival in patients. Together, these data underscore the potential for resistance of PDAC to even the very best of KRAS inhibitors and suggest combination therapies with PI3K inhibitors as a viable strategy to circumvent resistance. Overall design: KRAS intact and knockout subclones from human 8988T and mouse A13 parental cell lines. Biologic replicates include 4 intact and 3 knockout clones from 8988T and 2 intact and 2 knockout clones from A13.

INSTRUMENT(S): Illumina HiSeq 2000 (Homo sapiens)

SUBMITTER: A Bhutkar 

PROVIDER: GSE71876 | GEO | 2017-10-23

SECONDARY ACCESSION(S): PRJNA292392

REPOSITORIES: GEO

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