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  3. Investigating synthetic lethality and PARP inhibitor resistance in pancreatic cancer through enantiomer differential activity

Investigating synthetic lethality and PARP inhibitor resistance in pancreatic cancer through enantiomer differential activity

  • Cell Death Discov. 2025 Mar 16;11(1):106. doi: 10.1038/s41420-025-02382-3.
Mirco Masi # 1,  Laura Poppi # 2,  Viola Previtali # 1,  Shannon R Nelson 3,  Kieran Wynne 4 5,  Giulia Varignani 1,  Federico Falchi 1 2,  Marina Veronesi 6,  Ennio Albanesi 7,  Daniele Tedesco 8,  Francesca De Franco 9,  Andrea Ciamarone 1 2,  Samuel H Myers 1,  Jose Antonio Ortega 1,  Greta Bagnolini 2,  Giovanni Ferrandi 1 2,  Fulvia Farabegoli 2,  Nicola Tirelli 10,  Giuseppina Di Stefano 11,  Giorgio Oliviero 4,  Naomi Walsh 3,  Marinella Roberti 2,  Stefania Girotto 12 13,  Andrea Cavalli 14 15 16
Affiliations

Affiliations

  • 1 Computational and Chemical Biology, Italian Institute of Technology IIT, 16163, Genoa, Italy.
  • 2 Department of Pharmacy and Biotechnology, University of Bologna, 40126, Bologna, Italy.
  • 3 National Institute for Cellular Biotechnology, School of Biotechnology, Dublin City University, D09 NR58, Dublin, Ireland.
  • 4 Systems Biology Ireland, School of Medicine, University College Dublin, D04 V1W8, Dublin, Ireland.
  • 5 Conway Institute of Biomolecular & Biomedical Research, University College Dublin, D04 V1W8, Dublin, Ireland.
  • 6 Structural Biophysics Facility, Italian Institute of Technology IIT, 16163, Genoa, Italy.
  • 7 Department of Neuroscience and Brain Technologies, Neurofacility, Italian Institute of Technology IIT, 16163, Genoa, Italy.
  • 8 Institute for Organic Synthesis and Photoreactivity (ISOF), National Research Council of Italy (CNR), I-40129, Bologna, Italy.
  • 9 TES Pharma S.r.l., I-06073, Perugia, Italy.
  • 10 Laboratory for Polymers and Biomaterials, Italian Institute of Technology IIT, 16163, Genoa, Italy.
  • 11 Department of Surgical and Medical Sciences, University of Bologna, 40126, Bologna, Italy.
  • 12 Computational and Chemical Biology, Italian Institute of Technology IIT, 16163, Genoa, Italy. stefania.girotto@iit.it.
  • 13 Structural Biophysics Facility, Italian Institute of Technology IIT, 16163, Genoa, Italy. stefania.girotto@iit.it.
  • 14 Computational and Chemical Biology, Italian Institute of Technology IIT, 16163, Genoa, Italy. andrea.cavalli@iit.it.
  • 15 Department of Pharmacy and Biotechnology, University of Bologna, 40126, Bologna, Italy. andrea.cavalli@iit.it.
  • 16 Centre Européen de Calcul Atomique et Moléculaire (CECAM), Ecole Polytechnique Fédérale de Lausanne, 1015, Lausanne, Switzerland. andrea.cavalli@iit.it.
  • # Contributed equally.
PMID: 40091075 DOI: 10.1038/s41420-025-02382-3
Abstract

The RAD51-BRCA2 interaction is central to DNA repair through homologous recombination. Emerging evidence indicates RAD51 overexpression and its correlation with chemoresistance in various cancers, suggesting RAD51-BRCA2 inhibition as a compelling avenue for intervention. We previously showed that combining olaparib (a PARP Inhibitor (PARPi)) with RS-35d (a BRCA2-RAD51 inhibitor) was efficient in killing pancreatic ductal adenocarcinoma (PDAC) cells. However, RS-35d impaired cell viability even when administered alone, suggesting potential off-target effects. Here, through multiple, integrated orthogonal biological approaches in different 2D and 3D PDAC cultures, we characterised RS-35d enantiomers, in terms of mode of action and single contributions. By differentially inhibiting both RAD51-BRCA2 interaction and sensor kinases ATM, ATR and DNA-PK, RS-35d enantiomers exhibit a 'within-pathway synthetic lethality' profile. To the best of our knowledge, this is the first reported proof-of-concept single small molecule capable of demonstrating this built-in synergism. In addition, RS-35d effect on BRCA2-mutated, olaparib-resistant PDAC cells suggests that this compound may be effective as an Anticancer agent possibly capable of overcoming PARPi resistance. Our results demonstrate the potential of synthetic lethality, with its diversified applications, to propose new and concrete opportunities to effectively kill Cancer cells while limiting side effects and potentially overcoming emerging drug resistance.

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