Inhibitor of Apoptosis Proteins (IAPs) are commonly dysregulated in GIST and can be pharmacologically targeted to enhance the pro-apoptotic activity of imatinib
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Johanna Falkenhorst1, Susanne Grunewald1, Thomas Mühlenberg1, Adrian Marino-Enriquez4, Anna-Carina Reis1,2 Christopher Corless5, Michael Heinrich6, Jürgen Treckmann1,3, Lars Erik Podleska1,3, Martin Schuler1,7, Jonathan Alfred Fletcher4, Sebastian Bauer1,7
1Sarcoma Center, Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany
2Department of Pathology and Neuropathology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany
3Department of Surgery, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany
4Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA
5Department of Pathology, Oregon Health and Science University Knight Cancer Institute, Portland, OR, USA
6Department of Medical Oncology, Oregon Health and Science University Knight Cancer Institute, Portland, OR, USA
7German Cancer Consortium (DKTK), Heidelberg, Germany
Sebastian Bauer, e-mail: [email protected]
Keywords: GIST, inhibitors of apoptosis proteins, LCL161, TL32711, YM155
Received: July 17, 2015 Accepted: April 14, 2016 Published: May 4, 2016
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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