UBA1 inhibition sensitizes cancer cells to PARP inhibitors
Sharad Awasthi, Lacey E. Dobrolecki, Christina Sallas, Xudong Zhang, Li Yang, Sima Khazaei, Sumanta Ghosh, Collene 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
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. • Genome-wide CRISPR screening identifies synergy between UBA1 and PARP inhibition • UBA1 inhibition causes homologous recombination repair defects • UBA1 inhibition drives hyper-PARylation, which can be blocked by PARP inhibition • Combination of UBA1 and PARP inhibition shows no evidence of toxicity Awasthi et al. discover that UBA1 loss is synthetically lethal with PARP inhibition. Pharmacological inhibition of UBA1 prevents homologous recombination repair and drives hyper-PARylation, which can be blocked by PARP inhibition. They find that the combination of PARP and UBA1 inhibition is synergistic in numerous models and well tolerated in vivo .