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Insulin receptor substrate-1 deficiency drives a proinflammatory phenotype in KRAS mutant lung adenocarcinoma. | LitMetric

Insulin receptor substrate-1 deficiency drives a proinflammatory phenotype in KRAS mutant lung adenocarcinoma.

Proc Natl Acad Sci U S A

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109; Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109; Division of Pulmonary and Critical Care, University of Washington, Seattle, WA 98195

Published: August 2016

Insulin receptor substrate-1 (IRS-1) is a signaling adaptor protein that interfaces with many pathways activated in lung cancer. It has been assumed that IRS-1 promotes tumor growth through its ability to activate PI3K signaling downstream of the insulin-like growth factor receptor. Surprisingly, tumors with reduced IRS-1 staining in a human lung adenocarcinoma tissue microarray displayed a significant survival disadvantage, especially within the Kirsten rat sarcoma viral oncogene homolog (KRAS) mutant subgroup. Accordingly, adenoviral Cre recombinase (AdCre)-treated LSL-Kras/Irs-1(fl/fl) (Kras/Irs-1(-/-)) mice displayed increased tumor burden and mortality compared with controls. Mechanistically, IRS-1 deficiency promotes Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling via the IL-22 receptor, resulting in enhanced tumor-promoting inflammation. Treatment of Kras/Irs-1(+/+) and Kras/Irs-1(-/-) mice with JAK inhibitors significantly reduced tumor burden, most notably in the IRS-1-deficient group.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4978299PMC
http://dx.doi.org/10.1073/pnas.1601989113DOI Listing

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