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Abstract

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.