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.
Highlights
Gastrointestinal stromal tumors (GIST) are among the most commonly diagnosed mesenchymal tumors and are typically characterized by gain of function mutations in receptor tyrosine kinases (RTKs) KIT or PDGFRA [1, 2]
CIAP1 was expressed in 84% (n=19), survivin was expressed in 80%and XIAP in 75% of primary GIST (n=20; Figure 1A) and in all GIST cell lines (Figure 1B)
Expression levels were highest in rapidly growing GIST-T1 when compared to the average of primary tumors (XIAP 60% of GIST-T1, survivin 50% of GIST-T1 expression levels; Figure 1A) with exception of cIAP1, where expression levels were comparable to GIST-T1 with variable expression ranging from 27 to 200% of GIST-T1 expression levels
Summary
Gastrointestinal stromal tumors (GIST) are among the most commonly diagnosed mesenchymal tumors and are typically characterized by gain of function mutations in receptor tyrosine kinases (RTKs) KIT or PDGFRA [1, 2]. Treatment with the tyrosine kinase inhibitors (TKIs) imatinib (IM) and sunitinib (SU) has more than tripled the median overall survival. Secondary KIT mutations have been shown to confer imatinib resistance but mechanisms that help GIST cells to evade apoptosis despite effective KIT inhibition are not completely understood [5, 6]. Both autophagy and quiescence have been shown to protect GIST cells from apoptosis [7, 8, 9], but the role of Inhibitors of Apoptosis Proteins (IAPs) has not yet been studied in GIST
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