PARP inhibitors (PARPi) have received regulatory approval for the treatment of several tumors, including prostate cancer (PCa), and demonstrate remarkable results in the treatment of castration-resistant prostate cancer (CRPC) patients characterized by defects in homologous recombination repair (HRR) genes. Preclinical studies showed that DNA repair genes (DRG) other than HRR genes may have therapeutic value in the context of PARPi. To this end, we performed multiple CRISPR/Cas9 screens in PCa cell lines using a custom sgRNA library targeting DRG combined with PARPi treatment. We identified LIG1, EME1, and FAAP24 losses as PARPi sensitizers and assessed their frequencies from 3 to 6% among CRPC patients. We showed that concomitant inactivation of LIG1 and PARP induced replication stress and DNA double-strand breaks, ultimately leading to apoptosis. This synthetic lethality (SL) is conserved across multiple tumor types (e.g., lung, breast, and colorectal), and its applicability might be extended to LIG1-functional tumors through a pharmacological combinatorial approach. Importantly, the sensitivity of LIG1-deficient cells to PARPi was confirmed in vivo. Altogether, our results argue for the relevance of determining the status of LIG1, and potentially other non-HRR DRG for CRPC patient stratification and provide evidence to expand their therapeutic options.
The Journal of clinical investigation. 2024 Dec 24 [Epub ahead of print]
Giulia Fracassi, Francesca Lorenzin, Francesco Orlando, Ubaldo Gioia, Giacomo D'Amato, Arnau S Casaramona, Thomas Cantore, Davide Prandi, Frédéric R Santer, Helmut Klocker, Fabrizio d'Adda di Fagagna, Joaquin Mateo, Francesca Demichelis
Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy., Institute of Molecular Genetics, National Research Council, Pavia, Italy., Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital Campus, Barcelona, Spain., Department of Urology, Division of Experimental Urology, Medical University of Innsbruck, Innsbruck, Austria.