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.

Survivin is a novel transcription regulator of KIT and is downregulated by miRNA‐494 in gastrointestinal stromal tumors

“…Based on a report indicating that survivin expression decreases upon KIT inhibition, we investigated whether miR‐494 represses survivin expression independent of KIT . As previously reported, RNAi‐mediated KIT depletion induces a significant decrease in survivin expression, which is almost completely rescued by KIT overexpression.…”

“…CKS1B is a regulator that binds to the cyclin‐dependent kinases, which promotes G2 to M phase transition . Survivin is also a cell cycle regulator involved in mitosis and has potential clinical significance in GIST tumorigenesis . To validate whether these genes were directly regulated by miR‐494, reporter vectors were constructed by conjugating each TargetScan‐predicted miR‐494 binding site located in the 3′‐UTR regions of each gene with a luciferase expression vector (Fig.…”

Investigations on Apoptotic Activities of Cherry Laurel Extracts in HCT-116 Human Colon Carcinoma Cells

“…Consequently, apoptotic induction is of critical importance in the inhibition of cancer cell growth. 18 Selective treatments, which lead to apoptosis of cancer cells but do not negatively affect normal cells could be utilized along with chemotherapies and potentially could enhance their efficacy. 6 The ability of bioactive compounds in foods to suppress colorectal cancer growth and metastasis and induce apoptosis requires further analysis to clarify the mechanism of action.…”

“…6 The ability of bioactive compounds in foods to suppress colorectal cancer growth and metastasis and induce apoptosis requires further analysis to clarify the mechanism of action. 18 The regular consumption of isoflavones, anthocyanidins, flavones and flavonols is linked to reduced risk of colorectal cancer. 19 In a previous study, 20 the consumption of anthocyanin rich black raspberry powder lead to pronounced extents of suppression in colorectal cancers.…”

Gastrointestinal stromal tumors (GIST): Facing cell death between autophagy and apoptosis

“…67,74,94 However, the role of IAPs has only recently been investigated in GIST by Falkenhorst and coworkers. 102 The authors showed that 2 IAPs, XIAP/BIRC4 and BIRC5/survivin, are highly expressed both at the mRNA and protein level in primary GIST and cell line models. Interestingly, the authors also showed that IAP inhibitors may improve the apoptotic response to KIT inhibitors.…”