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

The DNA repair protein PARP-1 emerged as a valuable target in the treatment of tu-
mor 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 irinote-
can (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
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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
Cancers 2024, 16, 3441. https://doi.org/10.3390/cancers16203441 https://www.mdpi.com/journal/cancers
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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.