title: Insulin receptor substrate-1 deficiency drives a proinflammatory phenotype in KRAS mutant lung adenocarcinoma.
abstract: 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.
authors.affiliation: Department of Medicine, Fred Hutchinson Cancer Research Center, Seattle, WA 98109; Department of Pathology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109;
authors.forename: Heather E
authors.initials: HE
authors.lastname: Metz
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109; Institute of Experimental and Clinical Pharmacology, Medical University of Graz, 8036 Graz, Austria;
authors.forename: Julia
authors.initials: J
authors.lastname: Kargl
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109;
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Busch
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109;
authors.forename: Kyoung-Hee
authors.initials: KH
authors.lastname: Kim
authors.affiliation: University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; Department of Biostatistics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15261;
authors.forename: Brenda F
authors.initials: BF
authors.lastname: Kurland
authors.affiliation: University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261;
authors.forename: Shira R
authors.initials: SR
authors.lastname: Abberbock
authors.affiliation: Experimental Histopathology Shared Resource, Fred Hutchinson Cancer Research Center, Seattle, WA 98109;
authors.forename: Julie
authors.initials: J
authors.lastname: Randolph-Habecker
authors.affiliation: Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210;
authors.forename: Sue E
authors.initials: SE
authors.lastname: Knoblaugh
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261;
authors.forename: Jay K
authors.initials: JK
authors.lastname: Kolls
authors.affiliation: Division of Endocrinology, Boston Children's Hospital, Boston, MA 02115;
authors.forename: Morris F
authors.initials: MF
authors.lastname: White
authors.affiliation: 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 houghton@fredhutch.org.
authors.forename: A McGarry
authors.initials: AM
authors.lastname: Houghton
mesh_terms: D000072283:A549 Cells; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D018345:Mice, Knockout; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
chemical_list: C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; C117307:KRAS protein, human; D018123:Receptors, Interleukin; C415369:interleukin-22 receptor; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Kras; adenocarcinoma; insulin receptor substrate-1; lung