Open Access

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

  • Authors:
    • André Fedier
    • Nadia Maggi
    • Alessandra Tozzi
    • Muriel Disler
    • Ricardo Coelho
    • Francis Jacob
    • Viola Heinzelmann‑Schwarz
  • View Affiliations

  • Published online on: June 1, 2022     https://doi.org/10.3892/ijo.2022.5379
  • Article Number: 89
  • Copyright : © Fedier et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY 4.0].

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Abstract

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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July-2022
Volume 61 Issue 1

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Spandidos Publications style
Fedier A, Maggi N, Tozzi A, Disler M, Coelho R, Jacob F and Heinzelmann‑Schwarz V: Exposure to escalating olaparib does not induce acquired resistance to PARPi and to other chemotherapeutic compounds in ovarian cancer cell lines. Int J Oncol 61: 89, 2022
APA
Fedier, A., Maggi, N., Tozzi, A., Disler, M., Coelho, R., Jacob, F., & Heinzelmann‑Schwarz, V. (2022). Exposure to escalating olaparib does not induce acquired resistance to PARPi and to other chemotherapeutic compounds in ovarian cancer cell lines. International Journal of Oncology, 61, 89. https://doi.org/10.3892/ijo.2022.5379
MLA
Fedier, A., Maggi, N., Tozzi, A., Disler, M., Coelho, R., Jacob, F., Heinzelmann‑Schwarz, V."Exposure to escalating olaparib does not induce acquired resistance to PARPi and to other chemotherapeutic compounds in ovarian cancer cell lines". International Journal of Oncology 61.1 (2022): 89.
Chicago
Fedier, A., Maggi, N., Tozzi, A., Disler, M., Coelho, R., Jacob, F., Heinzelmann‑Schwarz, V."Exposure to escalating olaparib does not induce acquired resistance to PARPi and to other chemotherapeutic compounds in ovarian cancer cell lines". International Journal of Oncology 61, no. 1 (2022): 89. https://doi.org/10.3892/ijo.2022.5379