title: Elevated RET expression enhances EGFR activation and mediates EGFR inhibitor resistance in head and neck squamous cell carcinoma.
abstract: Co-activation of EGFR by alternative receptor tyrosine kinases (RTKs) might mediate resistance to EGFR inhibition in head and neck squamous cell carcinoma (HNSCC). Here we found a novel mechanism to improve the efficacy of EGFR inhibitor erlotinib on HNSCC.
  
  
  
  Immunohistochemistry, western blot, cell migration and invasion assays, cell proliferation, cell cycle analysis and in vivo serial transplantation assays were used to evaluate the role of RET on HNSCC cells.
  
  
  
  The elevated levels of a rearranged during transfection (RET) are observed in HNSCC and that high levels of RET correlate with increased tumor size, advanced tumor stage and decreased overall survival rate. The HNSCC cell proliferation and invasion were inhibited by RET knockdown in vitro and in vivo. The inhibition of RET expression markedly reduced EGFR phosphorylation and downstream EGFR signaling. The inhibition of RET signaling significantly increased the sensitivity of HNSCC cells to the EGFR inhibitor erlotinib in both in vitro and in vivo models.
  
  
  
  Our results offer a preclinical proof-of-concept supporting a role for RET signaling inhibition in a targeted therapeutic approach to improve the efficacy of EGFR inhibition in HNSCC.
authors.affiliation: Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China; Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, Shanghai 200011, China.
authors.forename: Chengzhong
authors.initials: C
authors.lastname: Lin
authors.affiliation: Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China; Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, Shanghai 200011, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
authors.affiliation: Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China; Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, Shanghai 200011, China.
authors.forename: Zhenhu
authors.initials: Z
authors.lastname: Ren
authors.affiliation: Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China; Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, Shanghai 200011, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Department of Oral Pathology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
authors.forename: Chunye
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China; Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, Shanghai 200011, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Yang
authors.affiliation: Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China; Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, Shanghai 200011, China.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China; Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, Shanghai 200011, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Cao
authors.affiliation: Department of Oral Pathology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
authors.forename: Lizhen
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China; Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, Shanghai 200011, China. Electronic address: wxwxw2004@126.com.
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China; Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, Shanghai 200011, China. Electronic address: jitong70@hotmail.com.
authors.forename: Tong
authors.initials: T
authors.lastname: Ji
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D010671:Phenylurea Compounds / Q000494:pharmacology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D000077195:Squamous Cell Carcinoma of Head and Neck; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C559147:regorafenib; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human
keywords: EGFR; HNSCC; RET; TKI resistance