Abstract 2087: Mechanistic studies reveal novel molecular insights on anticancer properties of F10 compound in human colon cancer cells

Abstract

Abstract Fluoropyrimidine (FP) drugs, mainly 5-Fluorouracil (5-FU), constitute the backbone of combination chemotherapy regimens (e.g. FOLFOX and FOLFIRI) for treating colorectal cancer (CRC) and provide a survival benefit for patients with stage II, III, and IV colorectal cancer. However, 5 year survival rate for CRC patients with metastatic disease is less than 10%. This dreadful situation suggests urgent need for novel and more potent FPs to improve the outcomes of these patients. We have developed novel fluoropyrimidine drug polymers (e.g. F10) that show promising antitumor activity in multiple pre-clinical models even while displaying reduced systemic toxicities. F10 is taken up by malignant cells via active transport compared to 5-Fluorouracil, which is taken up by diffusion in malignant and non-malignant cells. Additionally, F10 compound is primarily incorporated into DNA, and produced thymidylate synthase and topoisomerase toxic metabolites at greater levels, whereas 5-Fluorouracil is primarily incorporated into RNA, and only has about 5-10% production of active form of thymidylate synthase toxic metabolites. MMR is involved in repairing the DNA mismatches and FP drugs induced DNA damage. Interestingly, our studies show that F10 acts by different mechanisms compared to 5-FU. Particularly, F10 treated CRC cells exhibit replication stress as evidenced by paused and slow progression of replication forks and R-loops formation at the active transcriptional regions, suggesting replication and transcription dependent generation of DNA lesions in these cells. F10 treatment induced several fold increased DNA double strand breaks (DSB) as measured by COMET assays and about 1000 folds more cytotoxicity to CRC cells compared to 5-FU. Similarly, F10 treatment activated distinctive DNA damage responses in MMR proficient CRC cells compared MMR deficient cells. Additionally, our studies suggest F10 as a promising therapeutic agent for CRC therapy either alone or in combination with CHK1 and PARP inhibitors. Citation Format: Chinnadurai Mani, William Gmeiner, Komaraiah Palle. Mechanistic studies reveal novel molecular insights on anticancer properties of F10 compound in human colon cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2087.