2. Academic Validation
  3. Targeting PARP-1 and DNA Damage Response Defects in Colorectal Cancer Chemotherapy with Established and Novel PARP Inhibitors

Targeting PARP-1 and DNA Damage Response Defects in Colorectal Cancer Chemotherapy with Established and Novel PARP Inhibitors

  • Cancers (Basel). 2024 Oct 10;16(20):3441. doi: 10.3390/cancers16203441.
Philipp Demuth 1,  Lea Thibol 1,  Anna Lemsch 1,  Felix Potlitz 2,  Lukas Schulig 2,  Christoph Grathwol 3,  Georg Manolikakes 4,  Dennis Schade 5,  Vassilis Roukos 6,  Andreas Link 2,  Jörg Fahrer 1
Affiliations

Affiliations

  • 1 Department of Chemistry, Division of Food Chemistry and Toxicology, RPTU Kaiserslautern-Landau, 67663 Kaiserslautern, Germany.
  • 2 Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, University of Greifswald, 17489 Greifswald, Germany.
  • 3 Institute of Biological and Chemical Systems-Functional Molecular Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), 76344 Eggenstein-Leopoldshafen, Germany.
  • 4 Department of Chemistry, RPTU Kaiserslautern-Landau, 67663 Kaiserslautern, Germany.
  • 5 Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Christian-Albrechts-University of Kiel, 24118 Kiel, Germany.
  • 6 Institute of Molecular Biology, 55128 Mainz, Germany.
PMID: 39456536 DOI: 10.3390/cancers16203441
Abstract

The DNA repair protein PARP-1 emerged as a valuable target in the treatment of tumor entities with deficiencies of BRCA1/2, such as breast Cancer. More recently, the application of PARP inhibitors (PARPi) such as olaparib has been expanded to other Cancer entities including colorectal Cancer (CRC). We previously demonstrated that PARP-1 is overexpressed in human CRC and promotes CRC progression in a mouse model. However, acquired resistance to PARPi and cytotoxicity-mediated adverse effects limit their clinical applicability. Here, we detailed the role of PARP-1 as a therapeutic target in CRC and studied the efficacy of novel PARPi compounds in wildtype (WT) and DNA repair-deficient CRC cell lines together with the chemotherapeutics irinotecan (IT), 5-fluorouracil (5-FU), and oxaliplatin (OXA). Based on the ComPlat molecule archive, we identified novel PARPi candidates by molecular docking experiments in silico, which were then confirmed by in vitro PARP activity measurements. Two promising candidates (X17613 and X17618) also showed potent PARP-1 inhibition in a CRC cell-based assay. In contrast to olaparib, the PARPi candidates caused no PARP-1 trapping and, consistently, were not or only weakly cytotoxic in WT CRC cells and their BRCA2- or ATR-deficient counterparts. Importantly, both PARPi candidates did not affect the viability of nonmalignant human colonic epithelial cells. While both olaparib and veliparib increased the sensitivity of WT CRC cells towards IT, no synergism was observed for X17613 and X17618. Finally, we provided evidence that all PARPi (olaparib > veliparib > X17613 > X17618) synergize with chemotherapeutic drugs (IT > OXA) in a BRCA2-dependent manner in CRC cells, whereas ATR deficiency had only a minor impact. Collectively, our study identified novel lead structures with potent PARP-1 inhibitory activity in CRC cells but low cytotoxicity due to the lack of PARP-1 trapping, which synergized with IT in homologous recombination deficiency.

Keywords

DNA damage response; PARP-1; chemotherapy; colorectal cancer; synthetic lethality.

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