PARP-inhibitors in epithelial ovarian cancer: Actual positioning and future expectations

Vanacker, Hélène; Harter, Philipp; Labidi-Galy, Sana Intidhar; Banerjee, Susana; Oaknin, Ana; Lorusso, Domenica

doi:10.1016/j.ctrv.2021.102255

Cited by 28 publications

(26 citation statements)

References 102 publications

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Section: Discussionmentioning

confidence: 99%

“…With the approval of PARPi in both front-line and recurrent settings, including HGSOC [ 24 , 51 ], PARPi resistance is an emerging clinical problem. While HR deficiency is generally a biomarker of sensitivity, HR proficiency is in most cases a marker of resistance, even though PARPi’s clinical activity in HR-proficient tumors has also been reported [ 51 ]. Most of the mechanisms of PARPi resistance come from studies on the few in vitro models selected for acquired resistance and on tumor samples from PARPi pretreated patients.…”

Section: Discussionmentioning

confidence: 99%

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Combinations of ATR, Chk1 and Wee1 Inhibitors with Olaparib Are Active in Olaparib Resistant Brca1 Proficient and Deficient Murine Ovarian Cells

Chiappa

Guffanti

Anselmi

et al. 2022

Cancers

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Background: Poly(ADP-ribose) polymerases inhibitor (PARPi) have shown clinical efficacy in ovarian carcinoma, especially in those harboring defects in homologous recombination (HR) repair, including BRCA1 and BRCA2 mutated tumors. There is increasing evidence however that PARPi resistance is common and develops through multiple mechanisms. Methods: ID8 F3 (HR proficient) and ID8 Brca1-/- (HR deficient) murine ovarian cells resistant to olaparib, a PARPi, were generated through stepwise drug concentrations in vitro. Both sensitive and resistant cells lines were pharmacologically characterized and the molecular mechanisms underlying olaparib resistance. Results: In ID8, cells with a HR proficient background, olaparib resistance was mainly caused by overexpression of multidrug resistance 1 gene (MDR1), while multiple heterogeneous co-existing mechanisms were found in ID8 Brca1-/- HR-deficient cells resistant to olaparib, including overexpression of MDR1, a decrease in PARP1 protein level and partial reactivation of HR repair. Importantly, combinations of ATR, Chk1 and Wee1 inhibitors with olaparib were synergistic in sensitive and resistant sublines, regardless of the HR cell status. Conclusion: Olaparib-resistant cell lines were generated and displayed multiple mechanisms of resistance, which will be instrumental in selecting new possible therapeutic options for PARPi-resistant ovarian tumors.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Combinations of ATR, Chk1 and Wee1 Inhibitors with Olaparib Are Active in Olaparib Resistant Brca1 Proficient and Deficient Murine Ovarian Cells

Chiappa

Guffanti

Anselmi

et al. 2022

Cancers

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“…Indeed, the BRCA* cohort exhibited a median PFS of 4.3 (olaparib) versus 2.8 months (placebo) (HR = 0.57; 95% CI: 0.37–0.87; p = 0.022), while BRCA wt showed a median PFS of 5.3 (olaparib) versus 2.8 months (placebo) (HR = 0.43; 95% CI: 0.26–0.71; p = 0.002). This seminal work paved the way for “PARPi rechallenge” [ 120 ] and raised new questions regarding the deciphering of predictive markers.…”

Section: Emerging Strategies and Perspectives For Accurate And Dynami...mentioning

confidence: 99%

Toward More Comprehensive Homologous Recombination Deficiency Assays in Ovarian Cancer Part 2: Medical Perspectives

Quesada

Fabbro

Solassol

2022

Cancers

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High-grade serous ovarian cancer (HGSOC) is the most frequent and aggressive form of ovarian cancer, representing an important challenge for clinicians. Half of HGSOC cases have homologous recombination deficiency (HRD), which has specific causes (mainly alterations in BRCA1/2, but also other alterations encompassed by the BRCAness concept) and consequences, both at molecular (e.g., genomic instability) and clinical (e.g., sensitivity to PARP inhibitor) levels. Based on its prevalence and clinical impact, HRD status merits investigation. To date, three PARP inhibitors have received FDA/EMA approval. For some approvals, the presence of specific molecular alterations is required. Three companion diagnostic (CDx) assays based on distinct technical and medical considerations have received FDA approval to date. However, their use remains controversial due to their technical and medical limitations. In this companion and integrated review, we take a “bench-to-bedside” perspective on HRD definition and evaluation in the context of HGSOC. Part 1 of the review adopts a molecular perspective regarding technical considerations and the development of CDx. Part 2 focuses on the clinical impact of HRD evaluation, primarily through currently validated CDx and prescription of PARP inhibitors, outlining achievements, limitations and medical perspectives.

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“…PARP inhibitors are now well known and widely used in ovarian cancer patients, while more precise molecular markers are needed to select patients and monitor treatment response ( 3 ). Nakanishi et al.…”

Section: Ovarian Cancermentioning

confidence: 99%

Editorial: Advances of Targeted Therapy in Gynecologic Malignancies

et al. 2022

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PARP-inhibitors in epithelial ovarian cancer: Actual positioning and future expectations

Cited by 28 publications

References 102 publications

Combinations of ATR, Chk1 and Wee1 Inhibitors with Olaparib Are Active in Olaparib Resistant Brca1 Proficient and Deficient Murine Ovarian Cells

Combinations of ATR, Chk1 and Wee1 Inhibitors with Olaparib Are Active in Olaparib Resistant Brca1 Proficient and Deficient Murine Ovarian Cells

Toward More Comprehensive Homologous Recombination Deficiency Assays in Ovarian Cancer Part 2: Medical Perspectives

Editorial: Advances of Targeted Therapy in Gynecologic Malignancies

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