Abstract 3907: Birinapant co-treatments of colon cancer cell lines show consensus molecular subtype-specific synergistic effects

Abstract

Abstract Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. Despite recent advances, the treatment success differs strongly between colorectal cancer patients and new treatment options are urgently needed. Since most tumors avoid apoptosis by a dysregulation of Inhibitor of apoptosis proteins (IAPs), IAP inhibitors such as the SMAC mimetic birinapant are promising new drugs for the treatment of CRC. However, it is currently not possible to stratify for patients who might benefit from adjuvant therapy and those who need new treatments. In 2015, an international consortium unified six independent subtyping approaches and defined 4 distinct, so-called consensus molecular subtypes (CMS). The CMSs are the current gold standard for CRC subtyping and have some prognostic values. Nevertheless, whether the CMS classification can be used to estimate the treatment success is currently under investigation. This study aimed to evaluate the efficacy of treatments with the chemotherapeutics oxaliplatin and 5-fluoruracil (5-FU), TNFalpha, the SMAC-mimetic birinapant and a combination of these drugs. We selected 10 cell lines, representing the four CMSs, and treated them for 24h and 48h with the respective drugs. At both time points, we assessed the cell death by staining with Annexin V/PI followed by flow cytometric analysis of the cells. We were able to show that birinapant has very strong synergistic effects if used in combination with either oxaliplatin/5-FU or TNFalpha, but does not induce apoptosis alone. Importantly, the efficacy of the various co-treatments differed between the cell lines. These differences can, to some extent, be linked to the corresponding CMS of the cells. Cells belonging to the CMS1 subtype showed strong synergistic effects of birinapant and oxaliplatin/5-FU. In contrast, birinapant and TNFalpha co-treatments showed synergistic effects in CMS2 cells, but not in CMS1 cells. Cells belonging to the CMS3 subtype, however, showed a mixed but generally weak response to the co-treatments. Our results highlight birinapant as a promising drug for the treatment of CRC. Our data also suggest that CMSs not only have prognostic values but may also be used as patient stratification tools. Citation Format: Michael Fichtner, Emir Bozkurt, Katherine McAllister, Christopher McCann, Daniel Longley, Jochen H. Prehn. Birinapant co-treatments of colon cancer cell lines show consensus molecular subtype-specific synergistic effects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3907.