DNA repair gene mutations are frequent in castration-resistant prostate cancer (CRPC), suggesting eligibility for poly(ADP-ribose) polymerase inhibitor (PARPi) treatment. However, therapy resistance is a major clinical challenge and genes contributing to PARPi resistance are poorly understood. Using a genome-wide CRISPR-Cas9 knockout screen, this study aimed at identifying genes involved in PARPi resistance in CRPC. Based on the screen, we identified PARP1, and six novel candidates associated with olaparib resistance upon knockout. For validation, we generated multiple knockout populations/clones per gene in C4 and/or LNCaP CRPC cells, which confirmed that loss of PARP1, ARH3, YWHAE, or UBR5 caused olaparib resistance. PARP1 or ARH3 knockout caused cross-resistance to other PARPis (veliparib and niraparib). Furthermore, PARP1 or ARH3 knockout led to reduced autophagy, while pharmacological induction of autophagy partially reverted their PARPi resistant phenotype. Tumor RNA sequencing of 126 prostate cancer patients identified low ARH3 expression as an independent predictor of recurrence. Our results advance the understanding of PARPi response by identifying four novel genes that contribute to PARPi sensitivity in CRPC and suggest a new model of PARPi resistance through decreased autophagy.
Oncogene. 2022 Aug 06 [Epub ahead of print]
Malene Blond Ipsen, Ea Marie Givskov Sørensen, Emil Aagaard Thomsen, Simone Weiss, Jakob Haldrup, Anders Dalby, Johan Palmfeldt, Peter Bross, Martin Rasmussen, Jacob Fredsøe, Søren Klingenberg, Mads R Jochumsen, Kirsten Bouchelouche, Benedicte Parm Ulhøi, Michael Borre, Jacob Giehm Mikkelsen, Karina Dalsgaard Sørensen
Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark., Department of Biomedicine, Aarhus University, Aarhus, Denmark., Teitur Trophics, Aarhus, Denmark., Department of Clinical Medicine, Aarhus University, Aarhus, Denmark., Department of Pathology, Aarhus University Hospital, Aarhus, Denmark., Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark. .