title: Inhibitor of Apoptosis Proteins (IAPs) are commonly dysregulated in GIST and can be pharmacologically targeted to enhance the pro-apoptotic activity of imatinib.
abstract: Gastrointestinal stromal tumors (GIST) exhibit a strong oncogenic dependency on KIT and KIT inhibitors confer long lasting disease stabilization in the majority of patients. Nonetheless, KIT inhibition alone does not cure GIST as a subset of GIST cells evade apoptosis and eventually develop resistance. Inhibitors of Apoptosis Proteins (IAPs) may confer resistance to drug-induced apoptosis. We observed that the mRNA and protein of IAPs XIAP (BIRC4) and survivin (BIRC5) were highly expressed in primary GIST tumors and cell line models. Amplification of the respective gene loci (BIRC2, BIRC3, BIRC4, BIRC5) was detected in 47% of GIST studied by SNP arrays. Whole exome analyses revealed a mutation of SMAC(DIABLO) in a heavily pretreated patient. Both, survivin (rank 62-92/11.194 tested proteins) and XIAP (rank 106-557/11.194) were found to be essential proteins for survival in a synthetic lethality screen. Expression of XIAP and survivin decreased upon KIT inhibition and may play a role in KIT-regulated pro-survival signaling. SMAC-mimetic treatment with LCL161 and TL32711 reduced cIAP1 and XIAP expression. Survivin inhibitor YM155 lead to transcriptional repression of BIRC5/survivin (YM155) and induced apoptosis. Combinational treatment with KIT inhibitors (imatinib, regorafenib) enhanced the proapoptotic effect. These findings support the combination of KIT inhibition with IAP antagonists in GIST.
authors.affiliation: Sarcoma Center, Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Falkenhorst
authors.affiliation: Sarcoma Center, Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Grunewald
authors.affiliation: Sarcoma Center, Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mühlenberg
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Adrian
authors.initials: A
authors.lastname: Marino-Enriquez
authors.affiliation: Sarcoma Center, Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.|Department of Pathology and Neuropathology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Anna-Carina
authors.initials: AC
authors.lastname: Reis
authors.affiliation: Department of Pathology, Oregon Health and Science University Knight Cancer Institute, Portland, OR, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Corless
authors.affiliation: Department of Medical Oncology, Oregon Health and Science University Knight Cancer Institute, Portland, OR, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Heinrich
authors.affiliation: Sarcoma Center, Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.|Department of Surgery, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Treckmann
authors.affiliation: Sarcoma Center, Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.|Department of Surgery, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Lars Erik
authors.initials: LE
authors.lastname: Podleska
authors.affiliation: Sarcoma Center, Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schuler
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Jonathan Alfred
authors.initials: JA
authors.lastname: Fletcher
authors.affiliation: Sarcoma Center, Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bauer
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000068877:Imatinib Mesylate / Q000627:therapeutic use*; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics*; D058990:Molecular Targeted Therapy; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D051034:Inhibitor of Apoptosis Proteins; D047428:Protein Kinase Inhibitors; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit
keywords: GIST; LCL161; TL32711; YM155; inhibitors of apoptosis proteins