PARP inhibitor resistance in IDH1-mutant cancers due to loss of end protection factors, 53BP1 and REV7
Year: 2025
Type: article
Abstract: Acquired resistance presents a major challenge for targeted therapies, with initially responsive tumors eventually reverting underlying vulnerabilities. Our group recently reported that cancers harboring isocitrate dehydrogenase 1/2 (IDH1/2) mutations have defective recruitment of homology-directed repair (HDR) factors to sites of DNA damage and consequent sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPi), a vulnerability that is being tested in clinical trials. To probe potential mechanisms by which resistance to PARPi might arise in this setting, we modeled PARPi resistance in IDH-mutant tumors via serial transplantation of patient-derived xenografts in mice treated with PARPi. An analysis of candidate DNA repair factors in these resistant tumor populations identified downregulation of two end protection factors that are negative regulators of HDR, 53BP1, and REV7. Knockout of these factors by CRISPR-Cas9 in IDH1-mutant cancer cells conferred robust resistance to PARPi and restored HDR capacity. To overcome this resistance, we found that treatment with the receptor tyrosine kinase inhibitor, cediranib, previously reported to suppress expression of downstream HDR factors, resensitizes 53BP1 and REV7-knockout cells to PARPi treatment. Our findings identify key pathways driving PARPi resistance in IDH1-mutant cancers and highlight potential therapeutic strategies to overcome this resistance.
Source: NAR Cancer
Authors: Daniel Andrés Colón-Ríos, Jonathan Dow, Adam Krysztofiak, Yanfeng Liu, Faye A Rogers, Peter M Glazer
Institution: Yale University
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,583
OpenAlex ID: W4417075156