title: IAP antagonists sensitize murine osteosarcoma cells to killing by TNFα.
abstract: Outcomes for patients diagnosed with the bone cancer osteosarcoma have not improved significantly in the last four decades. Only around 60% of patients and about a quarter of those with metastatic disease survive for more than five years. Although DNA-damaging chemotherapy drugs can be effective, they can provoke serious or fatal adverse effects including cardiotoxicity and therapy-related cancers. Better and safer treatments are therefore needed. We investigated the anti-osteosarcoma activity of IAP antagonists (also known as Smac mimetics) using cells from primary and metastatic osteosarcomas that arose spontaneously in mice engineered to lack p53 and Rb expression in osteoblast-derived cells. The IAP antagonists SM-164, GDC-0152 and LCL161, which efficiently target XIAP and cIAPs, sensitized cells from most osteosarcomas to killing by low levels of TNFα but not TRAIL. RIPK1 expression levels and activity correlated with sensitivity. RIPK3 levels varied considerably between tumors and RIPK3 was not required for IAP antagonism to sensitize osteosarcoma cells to TNFα. IAP antagonists, including SM-164, lacked mutagenic activity. These data suggest that drugs targeting XIAP and cIAP1/2 may be effective for osteosarcoma patients whose tumors express abundant RIPK1 and contain high levels of TNFα, and would be unlikely to provoke therapy-induced cancers in osteosarcoma survivors.
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Victoria, Australia.
authors.forename: Tanmay M
authors.initials: TM
authors.lastname: Shekhar
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Victoria, Australia.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Miles
authors.affiliation: St. Vincent's Institute of Medical Research, Fitzroy, Australia; Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, Australia.
authors.forename: Ankita
authors.initials: A
authors.lastname: Gupte
authors.affiliation: St. Vincent's Institute of Medical Research, Fitzroy, Australia; Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, Australia.
authors.forename: Scott
authors.initials: S
authors.lastname: Taylor
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Victoria, Australia.
authors.forename: Brianna
authors.initials: B
authors.lastname: Tascone
authors.affiliation: St. Vincent's Institute of Medical Research, Fitzroy, Australia; Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, Australia.
authors.forename: Carl R
authors.initials: CR
authors.lastname: Walkley
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Victoria, Australia.
authors.forename: Christine J
authors.initials: CJ
authors.lastname: Hawkins
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D000075747:Baculoviral IAP Repeat-Containing 3 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology* / Q000633:toxicity; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D003510:Cyclohexanes / Q000494:pharmacology* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018345:Mice, Knockout; D012516:Osteosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D010641:Phenotype; D011758:Pyrroles / Q000494:pharmacology* / Q000633:toxicity; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology* / Q000633:toxicity; D014162:Transfection; D014230:Triazoles / Q000494:pharmacology* / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C107521:Birc4 protein, mouse; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003510:Cyclohexanes; D051034:Inhibitor of Apoptosis Proteins; C574246:LCL161; D011758:Pyrroles; D016160:Retinoblastoma Protein; C533467:SM 164; D053221:TNF-Related Apoptosis-Inducing Ligand; D013844:Thiazoles; C505654:Tnfsf10 protein, mouse; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; C579046:GDC-0152; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; C494834:Birc2 protein, mouse; C494835:Birc3 protein, mouse; D044767:Ubiquitin-Protein Ligases; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse; C485615:Ripk3 protein, mouse
keywords: IAP; RIP1; Smac; bone cancer; osteosarcoma