UBA1 Inhibition Sensitizes Cancer Cells to PARP Inhibitors

Authors

Sharad Awasthi
Lacey E Dobrolecki
Christina Sallas
Xudong Zhang
Yang Li
Sima Khazaei
Sumanta Ghosh
Collene R Jeter
Jinsong Liu
Gordon B Mills
Shannon N Westin
Michael T Lewis
Weiyi Peng
Anil K Sood
Timothy A Yap
S Stephen Yi
Daniel J McGrail
Nidhi Sahni

Publication Date

12-17-2024

Journal

Cell Reports Medicine

DOI

10.1016/j.xcrm.2024.101834

PMID

39626673

PMCID

PMC11722100

PubMedCentral® Posted Date

12-2-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Humans, Poly(ADP-ribose) Polymerase Inhibitors, Ubiquitin-Activating Enzymes, Animals, Cell Line, Tumor, Female, Mice, Xenograft Model Antitumor Assays, Ovarian Neoplasms, DNA Damage, CRISPR-Cas Systems, Poly(ADP-ribose) Polymerases, PARP inhibitors, ubiquitination, homologous recombination repair, breast cancer, ovarian cancer

Abstract

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.