SMARCA4 loss increases RNA Polymerase II pausing and elevates R-loops to inhibit BRCA1-mediated repair in ovarian cancer

  • Cancer Res. 2025 May 14. doi: 10.1158/0008-5472.CAN-24-3990.
Xianbing Zhu  1 ,  Zheng Fu  2 ,  Giulio Aceto  2 ,  Jonathan St-Germain  3 ,  Kexin Liu  2 ,  Azadeh Arabzadeh  2 ,  Yuxuan Qi  4 ,  Yibo Xue  2 ,  Leora Witkowski  5 ,  Elise Graulich  2 ,  Jutta Steinberger  2 ,  Selim Misirlioglu  6 ,  Nicklas Bassani  7 ,  Racim Sansal  2 ,  Amber Yasmeen  8 ,  Geneviève Morin  2 ,  Jingjie Guo  9 ,  Anie Monast  2 ,  Virginie Pilon  2 ,  Alica Valachová  10 ,  Kitty Pavlakis  11 ,  Lili Fu  12 ,  Walter H Gotlieb  13 ,  W Glenn McCluggage  14 ,  David Huntsman  9 ,  Alexander J R Bishop  15 ,  Douglas A Levine  16 ,  Morag Park  17 ,  Yemin Wang  9 ,  Brian Raught  3 ,  William D Foulkes  2 ,  Sidong Huang  2
Affiliations
  • 1. McGill University, Montreal, Canada.
  • 2. McGill University, Montreal, Quebec, Canada.
  • 3. University Health Network, Toronto, Ontario, Canada.
  • 4. University of British Columbia, Canada.
  • 5. McGill University Health Centre, Canada.
  • 6. New York University Langone Medical Center, United States.
  • 7. UT Health San Antonio, United States.
  • 8. Jewish General Hospital, Montreal, Canada.
  • 9. University of British Columbia, Vancouver, BC, Canada.
  • 10. University Hospital Trencin, Slovak Republic.
  • 11. IASO women's hospital, Maroussi, Greece.
  • 12. McGill University Health Centre, Montreal, Quebec, Canada.
  • 13. McGill University Jewish General Hospital, Montreal, Quebec, Canada.
  • 14. Belfast Health and Social Care Trust, Belfast, United Kingdom.
  • 15. Nationwide Children's Hospital, Columbus, OH, United States.
  • 16. Merck Research Laboratories, Rahway, NJ, United States.
  • 17. McGill University, Montreal, QC, Canada.
PMID: 40366633 DOI: 10.1158/0008-5472.CAN-24-3990
Abstract

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, aggressive Cancer affecting young women, driven by inactivating mutations in SMARCA4, a key SWI/SNF chromatin remodeling gene. To uncover its druggable vulnerabilities, we performed a compound screen and found that SCCOHT cells and tumors were sensitive to PARP inhibitors. Paradoxically, SCCOHT displayed BRCA-deficient traits despite retaining wild-type BRCA1 expression. Elevated R-loop in SCCOHT sequestered BRCA1, limiting its availability for DNA damage repair. Proximity-dependent biotin identification revealed that wild-type SMARCA4, but not its pathogenic variants, promoted RNA polymerase II (Pol II) elongation by mediating the assembly of the polymerase-associated factor 1 (PAF1) complex. Thus, SMARCA4 loss increased Pol II pausing, resulting in elevated R-loops and BRCA1 redistribution. The suppression of BRCA1 activity sensitized SMARCA4-deficient SCCOHT cells and tumors to PARP inhibitors, which was further enhanced by the addition of a CDK9 Inhibitor targeting Pol II elongation. Co-targeting PARP/CDK9 also elicited synergistic effects against Other undifferentiated ovarian Cancer cells with SMARCA4 loss. These findings link SMARCA4 loss to perturbed Pol II elongation and compromised DNA repair by BRCA1, providing a therapeutic opportunity to target SCCOHT and Other SWI/SNF-deficient ovarian cancers.

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