title: Blocks to thyroid cancer cell apoptosis can be overcome by inhibition of the MAPK and PI3K/AKT pathways.
abstract: Current treatment for recurrent and aggressive/anaplastic thyroid cancers is ineffective. Novel targeted therapies aimed at the inhibition of the mutated oncoprotein BRAF(V600E) have shown promise in vivo and in vitro but do not result in cellular apoptosis. TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a tumor-selective manner by activating the extrinsic apoptotic pathway. Here, we show that a TRAIL-R2 agonist antibody, lexatumumab, induces apoptosis effectively in some thyroid cancer cell lines (HTh-7, TPC-1 and BCPAP), while more aggressive anaplastic cell lines (8505c and SW1736) show resistance. Treatment of the most resistant cell line, 8505c, using lexatumumab in combination with the BRAF(V600E) inhibitor, PLX4720, and the PI3K inhibitor, LY294002, (triple-drug combination) sensitizes the cells by triggering both the extrinsic and intrinsic apoptotic pathways in vitro as well as 8505c orthotopic thyroid tumors in vivo. A decrease in anti-apoptotic proteins, pAkt, Bcl-xL, Mcl-1 and c-FLIP, coupled with an increase in the activator proteins, Bax and Bim, results in an increase in the Bax to Bcl-xL ratio that appears to be critical for sensitization and subsequent apoptosis of these resistant cells. Our results suggest that targeting the death receptor pathway in thyroid cancer can be a promising strategy for inducing apoptosis in thyroid cancer cells, although combination with other kinase inhibitors may be needed in some of the more aggressive tumors initially resistant to apoptosis.
authors.affiliation: Thyroid Cancer Research Laboratory, Unit of Endocrine Surgery Unit, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: V
authors.initials: V
authors.lastname: Gunda
authors.affiliation: 1] Department of Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA [2] Department of Molecular Cell Biology, Institute of Biochemistry of the Romanian Academy, Bucharest, Romania.
authors.forename: O
authors.initials: O
authors.lastname: Bucur
authors.affiliation: Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: J
authors.initials: J
authors.lastname: Varnau
authors.affiliation: Thyroid Cancer Research Laboratory, Unit of Endocrine Surgery Unit, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Vanden Borre
authors.affiliation: Thyroid Cancer Research Laboratory, Unit of Endocrine Surgery Unit, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Bernasconi
authors.affiliation: Department of Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Khosravi-Far
authors.affiliation: Thyroid Cancer Research Laboratory, Unit of Endocrine Surgery Unit, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Parangi
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002867:Chromones / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D009025:Morpholines / Q000008:administration & dosage; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D034622:RNA Interference; D013449:Sulfonamides / Q000008:administration & dosage; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D051017:Apoptosis Regulatory Proteins; D002867:Chromones; D007211:Indoles; D009025:Morpholines; C528407:PLX 4720; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C510234:lexatumumab; D058539:Phosphatidylinositol 3-Kinase; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt