%0 Generic
%A Schwickert, Jonas Norbert
%C Heidelberg
%D 2024
%F heidok:34627
%R 10.11588/heidok.00034627
%T Characterization of PARP inhibitor resistance in patient-derived ovarian cancer cell lines
%U https://archiv.ub.uni-heidelberg.de/volltextserver/34627/
%X Poly(ADP-ribose) polymerase inhibitors (PARPis) have exhibited significant efficacy in clinical  settings and thus shown promise as a therapeutic option for ovarian cancer patients with  BRCA mutations. However, the emergence of resistance to PARPis poses a substantial  challenge, limiting its long-term effectiveness. Consequently, understanding additional  resistance mechanisms is crucial to improve the treatment efficacy of PARPis.  In this thesis, I utilized patient-derived ovarian cancer cell lines initially screened for their  response to PARPi treatment. To induce resistance, the two most responsive cell lines were  subjected to multiple rounds of increasing concentrations of olaparib (the first approved  PARPi) treatment. Notably, both cell lines were Homologous Recombination (HR)-proficient,  making them theoretically unsuitable for PARPi treatment. Employing various molecular and  sequencing approaches, I investigated and characterized the acquired PARPi resistance  mechanism in these HR-proficient ovarian cancer cell lines.  Surprisingly, I did not detect a known resistance mechanism to PARPis, possibly due to the HR  proficiency of both resistant and sensitive cells. However, the olaparib-resistant cell lines  demonstrated cross-resistance to other PARPis (Pamiparib, Niraparib, Rucaparib, Talazoparib)  while remaining sensitive to DNA-damaging agents, suggesting a PARP-specific and DNA  repair-independent resistance mechanism. Yet, the precise mechanism underlying acquired  resistance to PARPis in both cell lines remains to be determined. Nonetheless, the observation  that HR-proficient cell lines can be susceptible to PARPi treatment may expand the potential  treatment scope of PARPis to patients traditionally excluded based on their HR status.  In summary, this study demonstrates that some HR-proficient cells can be vulnerable to PARPi  treatment and that the acquired resistance in these cell lines is independent of DNA repair  pathways.