CRISPR/Cas9 screens identify LIG1 as a sensitizer of PARP inhibitors in castration-resistant prostate cancer

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

doi:10.1172/JCI179393

¹Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy

²Institute of Molecular Genetics, National Research Council, Pavia, Italy

³Vall d'Hebron Institute of Oncology, Vall d’Hebron University Hospital Campus, Barcelona, Spain

⁴Department of Urology, Division of Experimental Urology, Medical University of Innsbruck, Innsbruck, Austria

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¹Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy

²Institute of Molecular Genetics, National Research Council, Pavia, Italy

³Vall d'Hebron Institute of Oncology, Vall d’Hebron University Hospital Campus, Barcelona, Spain

⁴Department of Urology, Division of Experimental Urology, Medical University of Innsbruck, Innsbruck, Austria

Find articles by Lorenzin, F. in: JCI | PubMed | Google Scholar

¹Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy

²Institute of Molecular Genetics, National Research Council, Pavia, Italy

³Vall d'Hebron Institute of Oncology, Vall d’Hebron University Hospital Campus, Barcelona, Spain

⁴Department of Urology, Division of Experimental Urology, Medical University of Innsbruck, Innsbruck, Austria

Find articles by Orlando, F. in: JCI | PubMed | Google Scholar

¹Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy

²Institute of Molecular Genetics, National Research Council, Pavia, Italy

³Vall d'Hebron Institute of Oncology, Vall d’Hebron University Hospital Campus, Barcelona, Spain

⁴Department of Urology, Division of Experimental Urology, Medical University of Innsbruck, Innsbruck, Austria

Find articles by Gioia, U. in: JCI | PubMed | Google Scholar

¹Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy

²Institute of Molecular Genetics, National Research Council, Pavia, Italy

³Vall d'Hebron Institute of Oncology, Vall d’Hebron University Hospital Campus, Barcelona, Spain

⁴Department of Urology, Division of Experimental Urology, Medical University of Innsbruck, Innsbruck, Austria

Find articles by D'Amato, G. in: JCI | PubMed | Google Scholar

¹Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy

²Institute of Molecular Genetics, National Research Council, Pavia, Italy

³Vall d'Hebron Institute of Oncology, Vall d’Hebron University Hospital Campus, Barcelona, Spain

⁴Department of Urology, Division of Experimental Urology, Medical University of Innsbruck, Innsbruck, Austria

Find articles by Casaramona, A. in: JCI | PubMed | Google Scholar

¹Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy

²Institute of Molecular Genetics, National Research Council, Pavia, Italy

³Vall d'Hebron Institute of Oncology, Vall d’Hebron University Hospital Campus, Barcelona, Spain

⁴Department of Urology, Division of Experimental Urology, Medical University of Innsbruck, Innsbruck, Austria

Find articles by Cantore, T. in: JCI | PubMed | Google Scholar

¹Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy

²Institute of Molecular Genetics, National Research Council, Pavia, Italy

³Vall d'Hebron Institute of Oncology, Vall d’Hebron University Hospital Campus, Barcelona, Spain

⁴Department of Urology, Division of Experimental Urology, Medical University of Innsbruck, Innsbruck, Austria

Find articles by Prandi, D. in: JCI | PubMed | Google Scholar |

¹Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy

²Institute of Molecular Genetics, National Research Council, Pavia, Italy

³Vall d'Hebron Institute of Oncology, Vall d’Hebron University Hospital Campus, Barcelona, Spain

⁴Department of Urology, Division of Experimental Urology, Medical University of Innsbruck, Innsbruck, Austria

Find articles by Santer, F. in: JCI | PubMed | Google Scholar

¹Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy

²Institute of Molecular Genetics, National Research Council, Pavia, Italy

³Vall d'Hebron Institute of Oncology, Vall d’Hebron University Hospital Campus, Barcelona, Spain

⁴Department of Urology, Division of Experimental Urology, Medical University of Innsbruck, Innsbruck, Austria

Find articles by Klocker, H. in: JCI | PubMed | Google Scholar |

¹Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy

²Institute of Molecular Genetics, National Research Council, Pavia, Italy

³Vall d'Hebron Institute of Oncology, Vall d’Hebron University Hospital Campus, Barcelona, Spain

⁴Department of Urology, Division of Experimental Urology, Medical University of Innsbruck, Innsbruck, Austria

Find articles by d’Adda di Fagagna, F. in: JCI | PubMed | Google Scholar

¹Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy

²Institute of Molecular Genetics, National Research Council, Pavia, Italy

³Vall d'Hebron Institute of Oncology, Vall d’Hebron University Hospital Campus, Barcelona, Spain

⁴Department of Urology, Division of Experimental Urology, Medical University of Innsbruck, Innsbruck, Austria

Find articles by Mateo, J. in: JCI | PubMed | Google Scholar |

¹Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy

²Institute of Molecular Genetics, National Research Council, Pavia, Italy

³Vall d'Hebron Institute of Oncology, Vall d’Hebron University Hospital Campus, Barcelona, Spain

⁴Department of Urology, Division of Experimental Urology, Medical University of Innsbruck, Innsbruck, Austria

Find articles by Demichelis, F. in: JCI | PubMed | Google Scholar |

J Clin Invest. https://doi.org/10.1172/JCI179393.
Copyright © 2024, Fracassi et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published December 24, 2024 - Version history

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.

Version 1 (December 24, 2024): In-Press Preview

CRISPR/Cas9 screens identify LIG1 as a sensitizer of PARP inhibitors in castration-resistant prostate cancer

Giulia Fracassi,¹ Francesca Lorenzin,¹ Francesco Orlando,¹ Ubaldo Gioia,² Giacomo D'Amato,¹ Arnau S. Casaramona,³ Thomas Cantore,¹ Davide Prandi,¹ Frédéric R. Santer,⁴ Helmut Klocker,⁴ Fabrizio d’Adda di Fagagna,² Joaquin Mateo,³ and Francesca Demichelis¹

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CRISPR/Cas9 screens identify LIG1 as a sensitizer of PARP inhibitors in castration-resistant prostate cancer

Giulia Fracassi,1 Francesca Lorenzin,1 Francesco Orlando,1 Ubaldo Gioia,2 Giacomo D'Amato,1 Arnau S. Casaramona,3 Thomas Cantore,1 Davide Prandi,1 Frédéric R. Santer,4 Helmut Klocker,4 Fabrizio d’Adda di Fagagna,2 Joaquin Mateo,3 and Francesca Demichelis1

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Giulia Fracassi,¹ Francesca Lorenzin,¹ Francesco Orlando,¹ Ubaldo Gioia,² Giacomo D'Amato,¹ Arnau S. Casaramona,³ Thomas Cantore,¹ Davide Prandi,¹ Frédéric R. Santer,⁴ Helmut Klocker,⁴ Fabrizio d’Adda di Fagagna,² Joaquin Mateo,³ and Francesca Demichelis¹