Inhibitor of Apoptosis Proteins (IAPs) are commonly dysregulated in GIST and can be pharmacologically targeted to enhance the pro-apoptotic activity of imatinib

Johanna Falkenhorst, Susanne Grunewald, Thomas Mühlenberg, Adrian Marino-Enriquez, Anna Carina Reis, Christopher Corless, Michael Heinrich, Jürgen Treckmann, Lars Erik Podleska, Martin Schuler, Jonathan Alfred Fletcher, Sebastian Bauer

Research output: Contribution to journalArticle

16 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)41390-41403
Number of pages14
JournalOncotarget
Volume7
Issue number27
DOIs
StatePublished - Jul 5 2016
Externally publishedYes

Fingerprint

Inhibitor of Apoptosis Proteins
Gastrointestinal Stromal Tumors
Apoptosis
X-Linked Inhibitor of Apoptosis Protein
Exome
Survival
Gene Amplification
Stromal Cells
Tumor Cell Line
Drug Resistance
Single Nucleotide Polymorphism
Imatinib Mesylate
Proteins
Messenger RNA
Mutation
Therapeutics

Keywords

  • GIST
  • inhibitors of apoptosis proteins
  • LCL161
  • TL32711
  • YM155

ASJC Scopus subject areas

  • Oncology

Cite this

Inhibitor of Apoptosis Proteins (IAPs) are commonly dysregulated in GIST and can be pharmacologically targeted to enhance the pro-apoptotic activity of imatinib. / Falkenhorst, Johanna; Grunewald, Susanne; Mühlenberg, Thomas; Marino-Enriquez, Adrian; Reis, Anna Carina; Corless, Christopher; Heinrich, Michael; Treckmann, Jürgen; Podleska, Lars Erik; Schuler, Martin; Fletcher, Jonathan Alfred; Bauer, Sebastian.

In: Oncotarget, Vol. 7, No. 27, 05.07.2016, p. 41390-41403.

Research output: Contribution to journalArticle

Falkenhorst, J, Grunewald, S, Mühlenberg, T, Marino-Enriquez, A, Reis, AC, Corless, C, Heinrich, M, Treckmann, J, Podleska, LE, Schuler, M, Fletcher, JA & Bauer, S 2016, 'Inhibitor of Apoptosis Proteins (IAPs) are commonly dysregulated in GIST and can be pharmacologically targeted to enhance the pro-apoptotic activity of imatinib', Oncotarget, vol. 7, no. 27, pp. 41390-41403. https://doi.org/10.18632/oncotarget.9159
Falkenhorst, Johanna ; Grunewald, Susanne ; Mühlenberg, Thomas ; Marino-Enriquez, Adrian ; Reis, Anna Carina ; Corless, Christopher ; Heinrich, Michael ; Treckmann, Jürgen ; Podleska, Lars Erik ; Schuler, Martin ; Fletcher, Jonathan Alfred ; Bauer, Sebastian. / Inhibitor of Apoptosis Proteins (IAPs) are commonly dysregulated in GIST and can be pharmacologically targeted to enhance the pro-apoptotic activity of imatinib. In: Oncotarget. 2016 ; Vol. 7, No. 27. pp. 41390-41403.
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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.",
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AU - Marino-Enriquez, Adrian

AU - Reis, Anna Carina

AU - Corless, Christopher

AU - Heinrich, Michael

AU - Treckmann, Jürgen

AU - Podleska, Lars Erik

AU - Schuler, Martin

AU - Fletcher, Jonathan Alfred

AU - Bauer, Sebastian

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