title: JWA down-regulates HER2 expression via c-Cbl and induces lapatinib resistance in human gastric cancer cells.
abstract: Human epidermal growth factor receptor 2 (HER2) targeted therapy is currently considered as the standard treatment for HER2-positive advanced gastric cancer (GC). However, unsatisfactory results of recent phase III clinical trials involving lapatinib suggested biomarkers for selection of patients. The aim of this study was to identify JWA as a biomarker for lapatinib resistance in GC cells and elucidate the underlying mechanisms. Lapatinib was effective to the intrinsic cisplatin-resistant GC cells. JWA activation conferred lapatinib unresponsiveness, but reversed cisplatin resistance in GC cells. Whereas, deletion of JWA significantly restored lapatinib suppression on proliferation and lapatinib-induced apoptosis. JWA-induced down-regulation of HER2 and activation of ERK phosphorylation led to lapatinib resistance. Furthermore, c-Cbl represented a novel mechanism for HER2 degradation enhanced by JWA in GC cells. Taken together, JWA is a potential predictive marker for lapatinib resistance, targeting the patients that may benefit from lapatinib treatment in human GC.
authors.affiliation: Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Ling
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Weiyou
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department of Molecular Cell Biology and Toxicology, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Fengming
authors.initials: F
authors.lastname: Yang
authors.affiliation: Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Qian
authors.affiliation: Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Tongpeng
authors.initials: T
authors.lastname: Xu
authors.affiliation: Department of Molecular Cell Biology and Toxicology, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Shouyu
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Molecular Cell Biology and Toxicology, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China.|Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Yongqian
authors.initials: Y
authors.lastname: Shu
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D006360:Heat-Shock Proteins / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D000077341:Lapatinib; D026901:Membrane Transport Proteins; D050721:Proto-Oncogene Proteins c-cbl / Q000502:physiology*; D011799:Quinazolines / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis* / Q000378:metabolism; D013274:Stomach Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology
chemical_list: D002945:Cisplatin; D006360:Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D000077341:Lapatinib; D026901:Membrane Transport Proteins; D050721:Proto-Oncogene Proteins c-cbl; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C484566:ARL6IP5 protein, human; C508053:ERBB2 protein, human; C067419:CBL protein, human
keywords: C-Cbl; HER2; JWA; gastric cancer; lapatinib