Abstract 599: Potential biomarkers of Smac mimetic tumor sensitivity: inhibitor of apoptosis protein DNA copy number.
Authors: Kapoor Gurpreet S. , Geier Brian , Neiman Eric M. , Mitsuuchi Yasuhiro , Benetatos Christopher A. , Condon Stephen M. , Chunduru Srinivas , Begley C. Glenn 
Published: August 2014

The inhibitor of apoptosis (IAP) family of proteins block programmed cell death and promote survival signaling. Birinapant (TL32711) is a bivalent Smac Mimetic that antagonizes multiple IAPs to promote efficient apoptosis and is currently in clinical trials as a single agent and in combination with multiple chemotherapeutics. However, to enrich for patient populations that will maximally benefit from each specific treatment regimen, it is critical to identify predictive biomarkers to achieve maximum response. Based on multiple individual studies, members of IAPs have been reported to be overexpressed in multiple cancers. Therefore, the main focus of this study was to evaluate DNA copy number alterations of different IAPs in a variety of cancer cell lines, and to evaluate their association with birinapant sensitivity. Our initial analysis of the Cancer Cell Line Encyclopedia (CCLE) database revealed that approximately 41% (397/972) of the cancer cell lines carried DNA amplification of different IAPs. Detailed analysis showed copy number amplification of ML-IAP in 214 cell lines (22%), cIAP1/2 in 85 cell lines (∼9%), NAIP (BIRC1) in 37 cell lines (∼4%), BIRC8 (ILP-2) in 39 cell lines (4%) and XIAP in 22 cell lines (∼2%). Tumor-type evaluation indicated that ∼50% pancreatic, ∼25% melanoma, ∼35% colorectal, ∼40% ovarian, and ∼7% AML cancer cell lines carried DNA amplification of different IAPs, indicating that IAPs are frequently amplified in cell lines of various cancer types. To understand the association of IAP amplification and birinapant sensitivity, we analyzed 94 cell lines present in the CCLE for birinapant sensitivity with or without TNF, and with or without TRAIL. Our analyses indicated that approximately 20% (19/94) of cancer cell lines were birinapant single-agent sensitive, and ∼80% (75/94) were single resistant cell lines. Furthermore, ∼50% (37/75) of the birinapant single resistant cell lines showed synergistic induction of apoptosis when birinapant was combined with either TNF or TRAIL ("synergy-positive"). Our analysis showed that the frequency of cIAP1/2 amplification in birinapant single-agent sensitive cell lines was 3-fold higher (4/19, 21%) than in single-agent resistant cancer cell lines (5/75, 7%). However, there was no difference in IAP gene amplification between birinapant "synergy-positive" and "synergy-negative" resistant cell lines. This lack of correlation with the synergistic response observed with the combination of birinapant plus either TNF or TRAIL implies the involvement of additional pathways that we are attempting to define. We will present a comprehensive dataset for the role of IAP gene amplification in birinapant tumor sensitivity.

Citation Format: Gurpreet S. Kapoor, Brian Geier, Eric M. Neiman, Yasuhiro Mitsuuchi, Christopher A. Benetatos, Stephen M. Condon, Srinivas Chunduru, C. Glenn Begley. Potential biomarkers of Smac mimetic tumor sensitivity: inhibitor of apoptosis protein DNA copy number. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 599. doi:10.1158/1538-7445.AM2013-599