title: Targeting Autophagy Sensitizes BRAF-Mutant Thyroid Cancer to Vemurafenib.
abstract: The RAF inhibitor vemurafenib has provided a major advance for the treatment of patients with BRAF-mutant metastatic melanoma. However, BRAF-mutant thyroid cancer is relatively resistant to vemurafenib, and the reason for this disparity remains unclear. Anticancer therapy-induced autophagy can trigger adaptive drug resistance in a variety of cancer types and treatments. To date, role of autophagy during BRAF inhibition in thyroid cancer remains unknown.
  
  
  
  In this study, we investigate if autophagy is activated in vemurafenib-treated BRAF-mutant thyroid cancer cells, and whether autophagy inhibition improves or impairs the treatment efficacy of vemurafenib.
  
  
  
  Autophagy level was determined by western blot assay and transmission electron microscopy. The combined effects of autophagy inhibitor and vemurafenib were assessed in terms of cell viability in vitro and tumor growth rate in vivo. Whether the endoplasmic reticulum (ER) stress was in response to vemurafenib-induced autophagy was also analyzed.
  
  
  
  Vemurafenib induced a high level of autophagy in BRAF-mutant thyroid cancer cells. Inhibition of autophagy by either a pharmacological inhibitor or interfering RNA knockdown of essential autophagy genes augmented vemurafenib-induced cell death. Vemurafenib-induced autophagy was independent of MAPK signaling pathway and was mediated through the ER stress response. Finally, administration of vemurafenib with the autophagy inhibitor hydroxychloroquine promoted more pronounced tumor suppression in vivo.
  
  
  
  Our data demonstrate that vemurafenib induces ER stress response-mediated autophagy in thyroid cancer and autophagy inhibition may be a beneficial strategy to sensitize BRAF-mutant thyroid cancer to vemurafenib.
authors.affiliation: Department of Surgical Oncology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.|Department of Surgery, New York Presbyterian Hospital and Weill Medical College of Cornell University, New York, New York, 10021.
authors.forename: Weibin
authors.initials: W
authors.lastname: Wang
authors.affiliation: Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, 10065; and.
authors.forename: Helen
authors.initials: H
authors.lastname: Kang
authors.affiliation: Department of Surgery, New York Presbyterian Hospital and Weill Medical College of Cornell University, New York, New York, 10021.|Department of Ophthalmology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China.
authors.forename: Yinu
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Surgery, New York Presbyterian Hospital and Weill Medical College of Cornell University, New York, New York, 10021.
authors.forename: Irene
authors.initials: I
authors.lastname: Min
authors.affiliation: Department of Surgery, New York Presbyterian Hospital and Weill Medical College of Cornell University, New York, New York, 10021.
authors.forename: Brian
authors.initials: B
authors.lastname: Wyrwas
authors.affiliation: Department of Surgery, New York Presbyterian Hospital and Weill Medical College of Cornell University, New York, New York, 10021.
authors.forename: Maureen
authors.initials: M
authors.lastname: Moore
authors.affiliation: Department of Surgical Oncology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
authors.forename: Lisong
authors.initials: L
authors.lastname: Teng
authors.affiliation: Department of Surgery, New York Presbyterian Hospital and Weill Medical College of Cornell University, New York, New York, 10021.
authors.forename: Rasa
authors.initials: R
authors.lastname: Zarnegar
authors.affiliation: Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, 10065; and.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Surgery, New York Presbyterian Hospital and Weill Medical College of Cornell University, New York, New York, 10021.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Fahey
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D013449:Sulfonamides / Q000494:pharmacology*; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D000077484:Vemurafenib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf