CHD1L Inhibitor OTI-611 Synergizes with Chemotherapy to Enhance Antitumor Efficacy and Prolong Survival in Colorectal Cancer Mouse Models.

ABSTRACT: Colorectal cancer (CRC) is one of the most prevalent and deadly forms of cancer. It is universally treated with a combination of the DNA damaging chemotherapy drugs irinotecan, 5-Fluorouracil (5-FU), and oxaliplatin. CHD1L is a novel oncogene that plays critical roles in chromatin remodeling and DNA damage repair, as well as the regulation of malignant gene expression. We show that an inhibitor of CHD1L, OTI-611, when combined with chemotherapy significantly increases DNA damage in CRC cell lines. OTI-611 also synergizes with SN-38, 5-FU, and oxaliplatin in killing CRC tumor organoids. We also demonstrate that, as in breast cancer, OTI-611 traps CHD1L, PARP1, and PARP2 onto chromatin. The entrapment of CHD1L causes the deprotection of PAR chains in the nucleus, ultimately resulting

SUBMITTER: Sala R 

PROVIDER: S-EPMC11641930 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature