title: RACK1 overexpression is linked to acquired imatinib resistance in gastrointestinal stromal tumor.
abstract: Although treatment with imatinib, which inhibits KIT and PDGFR, controls advanced disease in about 80% of gastrointestinal stromal tumor (GIST) patients, resistance to imatinib often develops. RACK1 (Receptor for Activated C Kinase 1) is a ribosomal protein that contributes to tumor progression by affecting proliferation, apoptosis, angiogenesis, and migration. Here, we found that c-KIT binds to RACK1 and increases proteasome-mediated RACK1 degradation. Imatinib treatment inhibits c-KIT activity and prevents RACK1 degradation, and RACK1 is upregulated in imatinib-resistant GIST cells compared to non-resistant parental cells. Moreover, Erk and Akt signaling were reactivated by imatinib in resistant GIST cells. RACK1 functioned as a scaffold protein and mediated Erk and Akt reactivation after imatinib treatment, thereby promoting GIST cell survival even in the presence of imatinib. Combined inhibition of KIT and RACK1 inhibited growth in imatinib-resistant GIST cell lines and reduced tumor relapse in GIST xenografts. These findings provide new insight into the role of RACK1 in imatinib resistance in GIST.
authors.affiliation: Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.|Institute of General Surgery, Fudan University, Shanghai, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.|Institute of General Surgery, Fudan University, Shanghai, China.
authors.forename: Anwei
authors.initials: A
authors.lastname: Xue
authors.affiliation: Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.|Institute of General Surgery, Fudan University, Shanghai, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Fang
authors.affiliation: Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.|Institute of General Surgery, Fudan University, Shanghai, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Shu
authors.affiliation: Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.|Institute of General Surgery, Fudan University, Shanghai, China.
authors.forename: Jiaqian
authors.initials: J
authors.lastname: Ling
authors.affiliation: Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Yingyong
authors.initials: Y
authors.lastname: Hou
authors.affiliation: Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.|Institute of General Surgery, Fudan University, Shanghai, China.
authors.forename: Kuntang
authors.initials: K
authors.lastname: Shen
authors.affiliation: Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.|Institute of General Surgery, Fudan University, Shanghai, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Qin
authors.affiliation: Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.|Institute of General Surgery, Fudan University, Shanghai, China.
authors.forename: Yihong
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.|Institute of General Surgery, Fudan University, Shanghai, China.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Qin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D000075370:Receptors for Activated C Kinase / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; C419368:RACK1 protein, human; D000075370:Receptors for Activated C Kinase; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit
keywords: KIT; RACK1; gastrointestinal stromal tumor; imatinib