title: Obatoclax and LY3009120 Efficiently Overcome Vemurafenib Resistance in Differentiated Thyroid Cancer.
abstract: Although the prognosis of differentiated thyroid cancer (DTC) is relatively good, 30-40% of patients with distant metastases develop resistance to radioactive iodine therapy due to tumor dedifferentiation. For DTC patients harboring BRAFV600Emutation, Vemurafenib, a BRAF kinase inhibitor, has dramatically changed the therapeutic landscape, but side effects and drug resistance often lead to termination of the single agent treatment. In the present study, we showed that either LY3009120 or Obatoclax (GX15-070) efficiently inhibited cell cycle progression and induced massive death of DTC cells. We established that BRAF/CRAF dimerization was an underlying mechanism for Vemurafenib resistance. LY3009120, the newly discovered pan-RAF inhibitor, successfully overcame Vemurafenib resistance and suppressed the growth of DTC cells in vitro and in vivo. We also observed that expression of anti-apoptotic Bcl-2 increased substantially following BRAF inhibitor treatment in Vemurafenib-resistant K1 cells, and both Obatoclax and LY3009120 efficiently induced apoptosis of these resistant cells. Specifically, Obatoclax exerted its anti-cancer activity by inducing loss of mitochondrial membrane potential (ΔΨm), dysfunction of mitochondrial respiration, reduction of cellular glycolysis, autophagy, neutralization of lysosomes, and caspase-related apoptosis. Furthermore, the cancer killing effects of LY3009120 and Obatoclax extended to two more Vemurafenib-resistant DTC cell lines, KTC-1 and BCPAP. Taken together, our results highlighted the potential value of LY3009120 for both Vemurafenib-sensitive and -resistant DTC and provided evidence for the combination therapy using Vemurafenib and Obatoclax for radioiodine-refractory DTC.
authors.affiliation: Department of Nuclear Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, 600# Yishan Road, 200233, Shanghai, China.
authors.forename: Wei-Jun
authors.initials: WJ
authors.lastname: Wei
authors.affiliation: Department of Nuclear Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, 600# Yishan Road, 200233, Shanghai, China.
authors.forename: Zhen-Kui
authors.initials: ZK
authors.lastname: Sun
authors.affiliation: Department of Nuclear Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, 600# Yishan Road, 200233, Shanghai, China.
authors.forename: Chen-Tian
authors.initials: CT
authors.lastname: Shen
authors.affiliation: Department of Nuclear Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, 600# Yishan Road, 200233, Shanghai, China.
authors.forename: Hong-Jun
authors.initials: HJ
authors.lastname: Song
authors.affiliation: Department of Nuclear Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, 600# Yishan Road, 200233, Shanghai, China.
authors.forename: Xin-Yun
authors.initials: XY
authors.lastname: Zhang
authors.affiliation: Department of Nuclear Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, 600# Yishan Road, 200233, Shanghai, China.
authors.forename: Zhong-Ling
authors.initials: ZL
authors.lastname: Qiu
authors.affiliation: Department of Nuclear Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, 600# Yishan Road, 200233, Shanghai, China.
authors.forename: Quan-Yong
authors.initials: QY
authors.lastname: Luo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004351:Drug Resistance; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D064593:Heterografts; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D008819:Mice, Nude; D010671:Phenylurea Compounds / Q000008:administration & dosage*; D055503:Protein Multimerization; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage*; D011758:Pyrroles / Q000008:administration & dosage*; D013449:Sulfonamides / Q000008:administration & dosage*; D013964:Thyroid Neoplasms / Q000188:drug therapy*; D016896:Treatment Outcome; D000077484:Vemurafenib
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007211:Indoles; C000600963:LY3009120; D010671:Phenylurea Compounds; D011743:Pyrimidines; D011758:Pyrroles; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf; C520962:obatoclax
keywords: Drug resistance; LY3009120.; Obatoclax; Thyroid cancer; Vemurafenib