title: PI3K/AKT/mTOR pathway is activated after imatinib secondary resistance in gastrointestinal stromal tumors (GISTs).
abstract: Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of the rapamycin (mTOR) pathway activation may be related to imatinib resistance; however, no study has focused on whether signal conduction of this pathway will change after imatinib resistance. A total of 111 GIST samples from 91 patients were used in this study, including 20 pairs of samples before and after imatinib treatment. Immunohistochemistry was performed on tissue for p-KIT (phospho-KIT), PTEN (phosphatase and tensin homolog deleted on chromosome ten), PI3K, phospho-AKT (p-AKT), phospho-4EBP1 (p-4EBP1) and phospho-S6 (p-S6RP). The activation of AKT/mTOR was significantly higher in imatinib secondary resistant GIST (53.1 %) than in imatinib-sensitive (27.1 %) and primary resistant GIST (33.3 %) (P = 0.049). In the analysis of 20 pairs of samples, comparing pre-imatinib GIST with on-treatment ones, the PI3K status was changed from inactivated to activated in four cases each in eight patients with effective imatinib and 12 patients whose secondary resistance happened, respectively. AKT/mTOR status was inactivated in pre-imatinib and on-treatment samples in eight patients with effective imatinib; however, the status of six patients was changed from inactivated to activated in 12 patients at the time of tumor progression. The negative expression of p-KIT was accompanied with PI3K pathway and/or AKT/mTOR pathway activity in some GISTs with secondary resistance. PI3K/AKT/mTOR pathway can be partly activated after imatinib secondary resistance in GIST. In this pathway, activation of AKT/mTOR is a more crucial factor, and PI3K activation may be the early part of secondary resistance.
authors.affiliation: Laboratory of Carcinogenesis and Translational Research for the Ministry of National Education, Department of GI Oncology, Peking University School of Oncology, Beijing Cancer Hospital & Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Yunzhi
authors.initials: Y
authors.lastname: Dang
authors.forename: Jing
authors.initials: J
authors.lastname: Gao
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Li
authors.forename: Jianling
authors.initials: J
authors.lastname: Zou
authors.forename: Lin
authors.initials: L
authors.lastname: Shen
mesh_terms: D019008:Drug Resistance, Neoplasm; D005260:Female; D005500:Follow-Up Studies; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D007124:Immunoenzyme Techniques; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D009367:Neoplasm Staging; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D015398:Signal Transduction; D015996:Survival Rate; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D000068877:Imatinib Mesylate; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D019009:Proto-Oncogene Proteins c-kit; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C494929:PTEN protein, human