{"doi":"10.3390/ijms252313160","title":"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 in cell death by CHD1Li-mediated PARthanatos, as measured by AIF translocation to the nucleus. Finally, the combination of low doses of OTI-611 with irinotecan significantly reduces tumor volume and extends survival in CRC xenograft mouse models compared to irinotecan alone. The combination of standard of care chemotherapy drugs with CHD1Li represents a promising advancement in future therapeutic strategies for CRC and other cancers driven by CHD1L.","journal":"International Journal of Molecular Sciences","year":2024,"id":458941,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9555,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":491596,"name":"Hector Esquer","orcid":"0000-0002-1911-1523","position":1,"is_corresponding":false},{"id":1099750,"name":"Timothy Kellett","orcid":"0009-0000-8585-4299","position":2,"is_corresponding":false},{"id":1099746,"name":"Sophia Clune","orcid":"0009-0007-2734-972X","position":3,"is_corresponding":false},{"id":1099747,"name":"Paul Awolade","orcid":"0000-0003-3995-121X","position":4,"is_corresponding":false},{"id":491597,"name":"Laura A. Pike","orcid":"0009-0001-5841-2257","position":5,"is_corresponding":false},{"id":469869,"name":"Qiong Zhou","orcid":"0000-0002-8240-0440","position":6,"is_corresponding":false},{"id":10995,"name":"Wells A. Messersmith","orcid":"0000-0003-2349-0885","position":7,"is_corresponding":false},{"id":469872,"name":"Daniel V. LaBarbera","orcid":"0000-0001-9460-3862","position":8,"is_corresponding":false},{"id":403011,"name":"Rita Sala","orcid":"0000-0002-4353-0736","position":0,"is_corresponding":true}],"reference_count":33,"raw_metadata":null,"created_at":"2026-07-19T02:03:50.608887Z","pmid":"39684869","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}