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Synthetic lethality between PBRM1 deficiency and PARP inhibitors: exploiting G2/M checkpoint arrest in colorectal

Mohd Tarequl Islam1,2, Haiwei Quan3, Shuangquan Chen1

  • 1Center for Cancer Immunology, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China.

Molecular Medicine (Cambridge, Mass.)
|June 6, 2026
PubMed
Abstract

Insights

Loss of Polybromo 1 (PBRM1) in cancer makes cells sensitive to PARP inhibitors. This study explored PBRM1-deficient colorectal cancer, finding PARP inhibitors induce DNA damage and apoptosis, supporting PBRM1 as a predictive biomarker.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Polybromo 1 (PBRM1) is a subunit of the PBAF chromatin-remodeling complex, frequently lost in cancers.
  • PBRM1 loss correlates with increased replication stress and DNA damage, suggesting reliance on compensatory repair pathways.
  • Targeted therapies for PBRM1-deficient cancers are limited, necessitating exploration of synthetic-lethal strategies.

Purpose of the Study:

  • To investigate if clinically used PARP inhibitors selectively target PBRM1-deficient colorectal cancer cells.
  • To elucidate the cell-cycle and stress-response mechanisms underlying this synthetic lethality.
  • To compare PARP inhibition with broader chromatin remodeler targeting in PBRM1-deficient models.

Main Methods:

  • Generated isogenic PBRM1 knockout HCT116 colorectal carcinoma cells using CRISPR/Cas9.
  • Conducted a compound screen of PARP inhibitors (olaparib, rucaparib) and chromatin remodeler inhibitors.
  • Utilized CCK-8 viability assays, colony-formation assays, and mechanistic analyses (flow cytometry for cell cycle and apoptosis).

Main Results:

  • PBRM1 loss conferred selective hypersensitivity to PARP inhibitors in colorectal cancer models.
  • PARP inhibition amplified DNA-damage signaling, induced G2/M cell-cycle arrest, and triggered apoptosis.
  • Stress-response genes, including CSRNP3, were upregulated following PARP inhibition.

Conclusions:

  • PBRM1 deficiency sensitizes cancer cells to PARP inhibitors, offering a potential precision medicine approach.
  • The observed sensitivity is context-dependent and not universal across all PBRM1-deficient models.
  • PBRM1 may serve as a predictive biomarker for PARP inhibitor response in specific cancer contexts.
Keywords:
HCT116PARP inhibitorsPBRM1 deficiencySWI/SNF chromatin remodeling complexesSynthetic lethality

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