AACR 2025 Poster 418

Assessment of PARP Inhibitor Sensitivity Through Organoid Panel Screening and Resistance Modeling Using CRISPR/Cas9 Genome Engineering

Lenno Krenning, Dorrith Verstegen, Noa Werndlij, Irene Drosou, Marten Hornsveld, Mariusz Madej, Hester Bange, Peter van Schaik, Ludovic Bourré and Marrit Putker

Inhibition of poly(ADP-ribose)polymerase (PARP) is synthetically lethal in cells with impaired homologous recombination (HR) DNA repair. Hence, PARP-inhibitors (PARPi) are used to treat tumors with disruptive mutations in HR factors. However, both pre-existing and acquired resistance mechanisms limit the clinical success of PARPi (1). This highlights the need to develop new drugs and/or treatment strategies. In turn, the development of new drugs requires the availability of PARPi-resistant organoid models.

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• How organoid panel screening captures the heterogeneous response to talazoparib that is also observed in patients
  
  
• How SLFN11 expression correlates with talazoparib efficacy in breast and lung organoids
  
  
• How CRIPSR/Cas9 can be utilized for modelling genetic resistance in organoid models

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