title: BIRC3 is a novel driver of therapeutic resistance in Glioblastoma.
abstract: Genome-wide analysis of glioblastoma (GBM) reveals pervasive aberrations in apoptotic signaling pathways that collectively contribute to therapeutic resistance. Inhibitors of apoptosis proteins (IAP) exert critical control on the terminal segment of apoptosis leading to apoptosis evasion. In this study, we uncover a unique role for BIRC3, as an IAP that is critical in GBM in response to therapy. Using the TCGA dataset of 524 unique samples, we identify BIRC3 is the only IAP whose differential expression is associated with long-term survival in GBM patients. Using patient tissue samples we further show that BIRC3 expression increases with recurrence. When extrapolated to a preclinical model of a human GBM cell line, we find an increase in BIRC3 expression in response to irradiation (RT) and temozolomide (TMZ) treatment. More importantly, we mechanistically implicate STAT3 and PI3K signaling pathways as drivers of RT-induced up-regulation of BIRC3 expression. Lastly, we demonstrate that both in-vivo and in-vitro BIRC3 up-regulation results in apoptosis evasion and therapeutic resistance in GBM. Collectively, our study identifies a novel translational and targetable role for BIRC3 expression as a predictor of aggressiveness and therapeutic resistance to TMZ and RT mediated by STAT3 and PI3K signaling in GBM.
authors.affiliation: Department of Neuro-Oncology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612 USA.|Department of Tumor Biology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612 USA.
authors.forename: Dapeng
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Medical Bioinformatics, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612 USA.
authors.forename: Anders
authors.initials: A
authors.lastname: Berglund
authors.affiliation: Department of Neuro-Oncology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612 USA.|Department of Tumor Biology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612 USA.
authors.forename: Rajappa S
authors.initials: RS
authors.lastname: Kenchappa
authors.affiliation: Department of Neuro-Oncology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612 USA.|Department of Tumor Biology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612 USA.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Forsyth
authors.affiliation: Department of Immunology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612 USA.|Department of Cutaneous Oncology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612 USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Mulé
authors.affiliation: Department of Neuro-Oncology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612 USA.|Department of Tumor Biology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612 USA.
authors.forename: Arnold B
authors.initials: AB
authors.lastname: Etame
mesh_terms: D000818:Animals; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D001932:Brain Neoplasms / Q000235:genetics / Q000628:therapy*; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics / Q000628:therapy*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics*; D051379:Mice; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011836:Radiation Tolerance; D011878:Radiotherapy; D050796:STAT3 Transcription Factor / Q000378:metabolism; D016019:Survival Analysis; D000077204:Temozolomide; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D051034:Inhibitor of Apoptosis Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D003606:Dacarbazine; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases; D019869:Phosphatidylinositol 3-Kinases; D000077204:Temozolomide