UBA1 inhibition sensitizes cancer cells to PARP inhibitors
Therapeutic strategies targeting the DNA damage response, such as poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi), have revolutionized cancer treatment in tumors deficient in homologous recombination (HR). However, overcoming innate and acquired resistance to PARPi remains a significant challenge. Here, we employ a genome-wide CRISPR knockout screen and discover that the depletion of ubiquitin-activating enzyme E1 (UBA1) enhances sensitivity to PARPi in HR-proficient ovarian cancer cells. We show that silencing or pharmacological inhibition of UBA1 sensitizes multiple cell lines and organoid models to PARPi. Mechanistic studies uncover that UBA1 inhibition not only impedes HR repair to sensitize cells to PARP inhibition but also increases PARylation, which may subsequently be targeted by PARP inhibition. In vivo experiments using patient-derived xenografts demonstrate that combining PARP and UBA1 inhibition provided significant survival benefit compared to individual therapies with no detectable signs of toxicity, establishing this combination approach as a promising strategy to extend PARPi benefit.
Authors
- Sumanta Ghosh
- Gordon Brent Mills (ORCID: https://orcid.org/0000-0002-0144-9614)
- Collene Jeter (ORCID: https://orcid.org/0000-0002-9627-4529)
- Christina Sallas (ORCID: https://orcid.org/0009-0005-2194-0522)
- Shannon N. Westin (ORCID: https://orcid.org/0000-0002-1922-0156)
- Sima Khazaei (ORCID: https://orcid.org/0000-0002-0929-9366)
- Michael T. Lewis (ORCID: https://orcid.org/0000-0002-6330-4007)
- Lacey E. Dobrolecki (ORCID: https://orcid.org/0000-0001-6839-629X)
- Sharad Awasthi (ORCID: https://orcid.org/0000-0003-2011-442X)
- Daniel J. McGrail (ORCID: https://orcid.org/0000-0002-6669-6069)
- Nidhi Sahni (ORCID: https://orcid.org/0000-0002-9155-5882)
- S. Stephen Yi (ORCID: https://orcid.org/0000-0003-0047-8103)
- Timothy Anthony Yap (ORCID: https://orcid.org/0000-0002-2154-3309)
- Weiyi Peng (ORCID: https://orcid.org/0000-0002-7785-6240)
- Jinsong Liu (ORCID: https://orcid.org/0000-0002-3239-6658)
- Li Yang (ORCID: https://orcid.org/0000-0002-3972-4298)
- Xudong Zhang (ORCID: https://orcid.org/0000-0003-1896-4898)
- Anil K. Sood
Institutions
- Cleveland Clinic (US)
- The University of Texas MD Anderson Cancer Center (US)
- Oregon Health & Science University (US)
- Baylor College of Medicine (US)
- Cleveland Clinic Lerner College of Medicine (US)
- University of Houston (US)
- The University of Texas at Austin (US)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2024-12-01
- DOI
- https://doi.org/10.1016/j.xcrm.2024.101834
- Citations
- 11
- Primary Topic
- PARP inhibition in cancer therapy
- Type
- article
- Field-Weighted Citation Impact
- 3.11
Funders
- American Cancer Society
- Susan G. Komen for the Cure
- Cancer Prevention and Research Institute of Texas
- Susan G. Komen
- Andrew Sabin Family Foundation
- Frank McGraw Memorial Chair in Cancer Research
- Ovarian Cancer Research Alliance
- National Cancer Institute