Synthetic lethality between PBRM1 deficiency and PARP inhibitors: exploiting G2/M checkpoint arrest in colorectal cancer
- Mol Med. 2026 Jun 6. doi: 10.1186/s10020-026-01525-1.
- 1. Center for Cancer Immunology, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China.
- 2. University of Chinese Academy of Sciences, Beijing, China.
- 3. Department of Biopharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Shenzhen University of Advanced Technology, Shenzhen, 518107, China.
- 4. Department of Gastroenterology and Hepatology, the First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China.
- 5. Center for Cancer Immunology, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China. [email protected].
- 6. Department of Biopharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Shenzhen University of Advanced Technology, Shenzhen, 518107, China. [email protected].
Background: Polybromo 1 (PBRM1), encoding the BAF180 subunit of the polybromo-associated BAF (PBAF) chromatin-remodeling complex, is commonly lost or mutated across malignancies. Despite its prevalence, tailored therapeutics for PBRM1-defective cancers remain limited. PBRM1 loss is associated with elevated replication stress and DNA damage responses, implying dependence on compensatory repair pathways. Given the lack of genotype-matched drugs, exploiting DNA-repair dependencies may provide a precision option for PBRM1-deficient disease. We pursued a synthetic-lethality strategy in colorectal Cancer to test whether clinically used PARP inhibitors selectively suppress PBRM1-deficient cells and to define the linked cell-cycle and stress-response mechanisms. We also compared PARP inhibition with broader chromatin-remodeler targeting.
Methods: Isogenic PBRM1-/- HCT116 colorectal carcinoma cells were generated by CRISPR/Cas9 lentiviral editing using sgRNAs cloned into lenti-CRISPR-V2. Knockout was confirmed by Western blotting, Sanger Sequencing, and RT-qPCR. A focused compound screen compared four agents PARP inhibitors olaparib and rucaparib, the multi-target chromatin remodeler inhibitor AU-24,118, and the SMARCA2/4-targeting degrader AU-1530 using dose-response CCK-8 viability assays and selectivity indices. We then validated our results by 12-day colony-formation assays. Mechanistic analyses measured drug-induced G2/M accumulation by propidium iodide staining and flow cytometry and quantified Apoptosis by Annexin V/PI dual staining, with significance assessed by t-test or two-way ANOVA.
Conclusions: PBRM1 loss confers selective hypersensitivity to PARP inhibitors, which intensify DNA-damage signaling, promote G2/M checkpoint arrest, trigger Apoptosis, and induce stress-response genes such as CSRNP3. Although this effect appears context-dependent and was not observed uniformly across all PBRM1-/- models tested. These results support further evaluation of PBRM1 as a potential predictive biomarker in defined molecular contexts rather than as a universal marker of PARP Inhibitor sensitivity.