Abstract C043: Discovery of new drug combinations for metastatic colorectal cancer

Abstract

Abstract Colorectal cancer (CRC) is the second most common cause of cancer-related death worldwide. Despite a range of therapeutic options, drug resistance remains a significant challenge in CRC treatment. Drug combination therapy offers an opportunity to enhance therapeutic responses. There are several combination drug options that have been used for CRC patients such as FOLFOX (5-FU + Oxaliplatin) and FOLFIRI (5-FU + Irinotecan). This study aimed to discover novel drug combinations for CRC by conducting high-throughput screening of 800 pharmacologically active compounds in combination with the three main chemotherapy backbones used in CRC treatment: 5-FU, SN-38, and Oxaliplatin. Initially, we performed a primary drug screen using 11 human CRC cell lines, resulting in the identification of 72 candidate drug combinations (24 candidates x 3 backbones) exhibiting synergistic effects. Subsequently, we validated these candidates in a subset of 5 cell lines. Among them, 24 drug combinations (8 candidates x 3 backbones) were selected and further evaluated in an expanded panel of 44 CRC cell lines to determine the spectrum of drug responses and identify potential mutation, gene and protein expression biomarkers, that could predict the efficacy of the drug combinations. We investigated the molecular mechanisms underlying the synergistic effects of final 4 candidates combined with chemotherapeutic agents. Chk1 inhibitor MK-8776 showed significantly higher synergy scores in combination with SN-38 in TP53 mutated cell lines, which was further validated by in vitro apoptosis analysis and in vivo xenograft models using TP53 wildtype and knockout isogenic CRC cell lines. MK-8776 abrogated SN-38-mediated G2 cell cycle arrest, resulting in an increased cytotoxicity. These findings highlight the potential of the combination treatment involving SN-38 and MK-8776 as a promising strategy for CRC patients with TP53 mutations. Citation Format: Eun-Jung In, Tao Tan, Dmitri Mouradov, Anuratha Sakthianandeswaren, Amanda Au, Kym Lowes, Oliver Sieber. Discovery of new drug combinations for metastatic colorectal cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C043.