title: KIT over-expression by p55PIK-PI3K leads to Imatinib-resistance in patients with gastrointestinal stromal tumors.
abstract: Imatinib is the first-line drug for gastrointestinal stromal tumors (GISTs), as mutated KIT is closely associated with the occurrence of GIST. However, Imatinib resistance (IMA-resistance) occurs inevitably in most GIST patients. Although the over-expression of KIT in GIST is one of the major factors contributing to IMA-resistance, the underlying mechanism is still unclear. In this study, we demonstrate that p55PIK, an isoform of phosphoinositide 3-kinase (PI3K), increases KIT expression, leading to IMA-resistance in GISTs by activating NF-κB signaling pathway. Furthermore, down-regulation of p55PIK significantly decreases KIT expression and re-sensitizes IMA-resistance-GIST cells to Imatinib in vitro and in vivo. Interestingly, the expression of both p55PIK and KIT proteins is significantly increased in tumor samples from IMA-resistance-GIST patients, suggesting that p55PIK up-regulation may be important for IMA-resistance in the clinical setting. Altogether, our data provide evidence that p55PIK-PI3K signaling can contribute to IMA-resistance in GIST by increasing KIT expression. Moreover, p55PIK may be a novel potential drug target for treating tumors that develop IMA-resistance.
authors.affiliation: Department of Gastrointestinal Surgery Center, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Senyan
authors.initials: S
authors.lastname: Lai
authors.affiliation: Department of Gastrointestinal Surgery Center, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Guihua
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Gastrointestinal Surgery Center, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Xiaonian
authors.initials: X
authors.lastname: Cao
authors.affiliation: Department of Gastrointestinal Surgery Center, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Xuelai
authors.initials: X
authors.lastname: Luo
authors.affiliation: Department of Pathology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Guoping
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Bioengineering, Hubei University of Technology, Wuhan, 430068, China.
authors.forename: Xianmin
authors.initials: X
authors.lastname: Xia
authors.affiliation: Department of Gastrointestinal Surgery Center, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Junbo
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D008819:Mice, Nude; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D000068877:Imatinib Mesylate; D019869:Phosphatidylinositol 3-Kinases; C523442:PIK3R3 protein, human; D019009:Proto-Oncogene Proteins c-kit
keywords: Imatinib resistance; gastrointestinal stromal tumors; p55PIK