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- W2809720403 abstract "Introduction Colorectal cancer (CRC) is a worldwide cause of death and requires better treatment options. The stratification of CRC cell-lines into tumour representative molecular subtypes may improve drug screening in-vitro to identify improved chemotherapeutics. The CRIS classifier identifies five ‘CRC intrinsic subtypes’ within the cancer cell transcriptome: A, B, C, D and E. This classifier improves cell line subtype mapping by considering only tumour cell transcripts. The inhibitor of apoptosis (IAP) proteins are promising targets in personalised medicine as CRC tumours dysregulate IAPs to avoid apoptosis. This study explored the efficacy of Birinapant - a potent SMAC mimetic and antagonist of IAPs, along with synergistic agents to promote optimal cell death in vitro using a model of CRC intrinsic subtypes. Material and methods The CRIS classifier analysis was performed on 150 CRC cell transcriptomes to select 10 cell lines: CRIS A (DLD-1, LS174T), CRIS B (LoVo, HT29), CRIS C (Gp5D, LIM1215), CRIS D (HCT116, RKO) and CRIS E (HCT116 p53-/-, LS513). The cells were treated with 1 µM Birinapant alone, and/or the cytotoxic pair Oxaliplatin and 5-Fluorouracil (2 µM, 10 µM), and/or TNF-alpha. Post-treatment cellular sensitivity was measured at 24, 48 and 72 hours by assessing Annexin V/Propidium Iodide positivity using high content microscopy. Results and discussions The cell death data from the entire panel showed that Birinapant cannot induce apoptosis when administered alone. However, Birinapant elicits synergistic effects in combination with Oxaliplatin/5-Flourouracil, or the pro-inflammatory cytokine TNF-alpha. The greatest degree of sensitivity was observed in the HCT116 and RKO CRIS D cell lines and least in the DLD1 and HT29 CRIS A subtypes. Of note, the p53-deficient HCT116 CRIS E model was less sensitive to the combined effects of Birinapant and chemotherapy, suggesting an important role for p53 in mediating this synergy. Conclusion Future work will expand the analysis to more CRIS D cell lines and investigate the molecular mechanisms behind the p53-dependence of the chemotherapy/IAP antagonist interactions. These results have clinical relevance as in parallel studies, we have shown that patients with CRIS D subtype tumours have a suboptimal response to standard-of-care chemotherapy.1 Reference 1. WL Allen et al., JCO Precision Oncology, 2018 (in press)" @default.
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- W2809720403 date "2018-06-01" @default.
- W2809720403 modified "2023-09-28" @default.
- W2809720403 title "PO-523 Sensitivity of colorectal cancer (CRC) CRIS subtypes to SMAC mimetic birinapant with standard of care chemotherapeutics: implications for personalised medicine" @default.
- W2809720403 doi "https://doi.org/10.1136/esmoopen-2018-eacr25.538" @default.
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