Exposure to escalating olaparib does not induce acquired resistance to PARPi and to other chemotherapeutic compounds in ovarian cancer cell lines

Poly (ADP‑ribose) polymerase (PARP)‑inhibitors (PARPi) such as olaparib and niraparib are currently used as a treatment option for BRCA‑deficient tumors and also show efficacy in platinum‑sensitive tumors. However, resistance to PARPi occurs in numerous patients and in particular acquired PARPi resistance presents a major obstacle in the treatment of these tumors. In the present study, it was investigated whether stepwise exposure of ovarian cancer cells to escalating concentrations of olaparib produced subcells with acquired resistance to PARPi and/or acquired cross‑resistance to platinum compounds, paclitaxel, and doxorubicin. To this aim, the sensitivity of fourteen ovarian cancer cell lines, including nine with TP53‑mutations and five carrying BRCA‑mutations, to olaparib and niraparib was determined and a subset of seven cell lines was selected to investigate the potential of olaparib to produce resistance. It was identified that escalating olaparib did neither produce subcells with acquired PARPi‑resistance nor did it produce acquired cross‑resistance to platinum compounds, doxorubicin, and paclitaxel. This finding was independent of the cells' TP53 and BRCA mutation status. CRISPR‑Cas9 mediated deletion of PARP1 did not affect sensitivity to PARPi, platinum compounds, doxorubicin, and paclitaxel. In addition, olaparib sensitivity correlated with niraparib sensitivity, but BRCA‑mutated cells were not more sensitive to PARPi. Moreover, PARPi sensitivity associated with cross‑sensitivity not only to platinum compounds but also to anthracylines, paclitaxel, and inhibitors of histone deacetylases. These in vitro data indicated that olaparib exposure is unlikely to produce an acquired resistance phenotype and that PARPi‑sensitive ovarian cancer cells are also cross‑sensitive to non‑platinum and even to compounds not directly interacting with the DNA.

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S2741 Niraparib (MK-4827) Niraparib (MK-4827) is a selective inhibitor of PARP1/2 with IC50 of 3.8 nM/2.1 nM, with great activity in cancer cells with mutant BRCA-1 and BRCA-2. It is >330-fold selective against PARP3, V-PARP and Tank1. Niraparib can form PARP–DNA complexes resulting in DNA damage, apoptosis, and cell death. Phase 3.

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Apoptosis related PARP