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 1 , Susanne Grunewald 1 , Thomas Mühlenberg 1 , Adrian Marino-Enriquez 4 , Anna-Carina Reis 1, 2 Christopher Corless 5 , Michael Heinrich 6 , Jürgen Treckmann 1, 3 , Lars Erik Podleska 1, 3 , Martin Schuler 1, 7 , Jonathan Alfred Fletcher 4 , Sebastian Bauer 1, 7 1 Sarcoma Center, Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany 2 Department of Pathology and Neuropathology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany 3 Department of Surgery, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany 4 Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA 5 Department of Pathology, Oregon Health and Science University Knight Cancer Institute, Portland, OR, USA 6 Department of Medical Oncology, Oregon Health and Science University Knight Cancer Institute, Portland, OR, USA 7 German Cancer Consortium (DKTK), Heidelberg, Germany Correspondence to: Sebastian Bauer, e-mail: sebastian.bauer@uk-essen.de Keywords: GIST, inhibitors of apoptosis proteins, LCL161, TL32711, YM155 Received: July 17, 2015      Accepted: April 14, 2016      Published: May 4, 2016 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.