title: mTOR inhibition elicits a dramatic response in PI3K-dependent colon cancers.
abstract: The phosphatidylinositide-3-kinase (PI3K) signaling pathway is critical for multiple cellular functions including metabolism, proliferation, angiogenesis, and apoptosis, and is the most commonly altered pathway in human cancers. Recently, we developed a novel mouse model of colon cancer in which tumors are initiated by a dominant active PI3K (FC PIK3ca). The cancers in these mice are moderately differentiated invasive mucinous adenocarcinomas of the proximal colon that develop by 50 days of age. Interestingly, these cancers form without a benign intermediary or aberrant WNT signaling, indicating a non-canonical mechanism of tumorigenesis. Since these tumors are dependent upon the PI3K pathway, we investigated the potential for tumor response by the targeting of this pathway with rapamycin, an mTOR inhibitor. A cohort of FC PIK3ca mice were treated with rapamycin at a dose of 6 mg/kg/day or placebo for 14 days. FDG dual hybrid PET/CT imaging demonstrated a dramatic tumor response in the rapamycin arm and this was confirmed on necropsy. The tumor tissue remaining after treatment with rapamycin demonstrated increased pERK1/2 or persistent phosphorylated ribosomal protein S6 (pS6), indicating potential resistance mechanisms. This unique model will further our understanding of human disease and facilitate the development of therapeutics through pharmacologic screening and biomarker identification.
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Dustin A
authors.initials: DA
authors.lastname: Deming
authors.forename: Alyssa A
authors.initials: AA
authors.lastname: Leystra
authors.forename: Mohammed
authors.initials: M
authors.lastname: Farhoud
authors.forename: Laura
authors.initials: L
authors.lastname: Nettekoven
authors.forename: Linda
authors.initials: L
authors.lastname: Clipson
authors.forename: Dawn
authors.initials: D
authors.lastname: Albrecht
authors.forename: Mary Kay
authors.initials: MK
authors.lastname: Washington
authors.forename: Ruth
authors.initials: R
authors.lastname: Sullivan
authors.forename: Jamey P
authors.initials: JP
authors.lastname: Weichert
authors.forename: Richard B
authors.initials: RB
authors.lastname: Halberg
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D058534:Class I Phosphatidylinositol 3-Kinases / Q000378:metabolism; D003106:Colon / Q000473:pathology; D003110:Colonic Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism*; D019788:Fluorodeoxyglucose F18; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D064847:Multimodal Imaging; D009336:Necrosis; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D049268:Positron-Emission Tomography; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014057:Tomography, X-Ray Computed
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D019788:Fluorodeoxyglucose F18; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; C546639:Pik3ca protein, mouse