Basal expression of RAD51 foci predicts olaparib response in patient-derived ovarian cancer xenografts

Guffanti, Federica; Alvisi, M.F.; Anastasia, Alessia; Ricci, Francesca; Chiappa, Michela; Llop‐Guevara, Alba; Serra, Violeta; Fruscio, Robert; Degasperi, Andrea; Nik-Zainal, Serena; Bani, Maria Rosa; Lupia, Michela; Giavazzi, Raffaella; Rulli, Eliana; Damia, Giovanna

doi:10.1038/s41416-021-01609-1

Cited by 26 publications

(28 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…According to the Cancer Genome Atlas (TCGA) consortium, more than half of HGSOC have homologous recombination (HR) deficiency due to mutations in genes involved in this pathway, including BRCA1 and 2 [ 7 ]. The synthetic lethality between HR deficiency and PARP inhibition [ 8 , 9 ] is at the basis of the strong antitumor activity of PARPi in HR-deficient tumors [ 10 , 11 ]. PARP enzymes catalyze the addition of poly(ADP-ribose) adducts to target proteins involved in cell signaling and DNA damage response, and their inhibition leads to accumulation of DNA single strand breaks (SSBs) and to a stall of replication forks, eventually progressing to double strand breaks (DSBs), which are highly cytotoxic to cells lacking a proficient HR [ 12 ].…”

Section: Introductionmentioning

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…#124R and #266R were obtained through multiple in vivo DDP rounds (six to eight DDP cycles) of treatment, as reported. 29 , 30 The main histological and molecular characteristics of the PDXs under studied are summarized in Supplementary Table 1 .…”

Section: Resultsmentioning

confidence: 99%

Onvansertib and paclitaxel combined in platinum-resistant ovarian carcinomas

et al. 2022

View full text Add to dashboard Cite

Background: Ovarian carcinoma is extremely sensitive to (platinum-based) chemotherapy; however, most patients will relapse with platinum-resistant disease, badly affecting their prognosis. Effective therapies for relapsing resistant tumors are urgently needed. Methods: We used patient-derived xenografts (PDXs) of ovarian carcinoma resistant to cisplatin (DDP) to test in vivo the combination of paclitaxel (15 mg/kg i.v. once a week for 3 weeks) and onvansertib, a plk1 inhibitor, (50 mg/kg orally 4 days a week for 3 weeks). The PDX models were subcutaneously (s.c.) or orthotopically transplanted in nude mice and antitumor efficacy was evaluated as tumor growth inhibition and survival advantages of the combination over untreated and single agent treatment. Results: The combination of onvansertib and paclitaxel was very well tolerated with weight loss no greater than 15% in the combination group compared with the control group. In the orthotopically transplanted PDXs, single onvansertib and paclitaxel treatments prolonged survival; however, the combined treatment was much more active, with median survival from three- to six-fold times that of untreated mice. Findings were similar with the s.c. transplanted PDX, though there was greater heterogeneity in tumor response. Ex vivo tumors treated with the combination showed greater induction of γH2AX, marker of apoptosis and DNA damage, and pSer10H3, a marker of mitotic block. Conclusion: The efficacy of onvansertib and paclitaxel combination in these preclinical ovarian cancer models supports the clinical translatability of this combination as an effective therapeutic approach for platinum-resistant high-grade ovarian carcinoma.

show abstract

“…It has been well-established that Rad51 functions as a promising predictor for the identification of PARP inhibitor-sensitive tumors in multiple tumor types ( 47 ). Basal Rad51 foci score acts as a candidate predictive biomarker of olaparib response in ovarian cancer patient-derived xenografts ( 48 ). Cruz et al.…”

Section: Role Of Rad51 In Tumorigenesis and Progressionmentioning

confidence: 99%

“…It has been well-established that Rad51 functions as a promising predictor for the identification of PARP inhibitorsensitive tumors in multiple tumor types (47). Basal Rad51 foci score acts as a candidate predictive biomarker of olaparib response in ovarian cancer patient-derived xenografts (48). Cruz et al found that low Rad51 expression was correlated with objective response to PARP inhibitors in germline BRCAmutated tumors, indicating Rad51 as a valuable biomarker to select patients eligible for treatment of PARP inhibitors (49).…”

Section: Rad51 and Resistance To Parp Inhibitorsmentioning

confidence: 99%

The Emerging Roles of Rad51 in Cancer and Its Potential as a Therapeutic Target

Wang

Jia²,

Wang³

et al. 2022

Front. Oncol.

View full text Add to dashboard Cite

Defects in DNA repair pathways are emerging hallmarks of cancer. Accurate DNA repairs and replications are essential for genomic stability. Cancer cells require residual DNA repair capabilities to repair the damage from replication stress and genotoxic anti-tumor agents. Defective DNA repair also promotes the accumulation of genomic changes that eventually lead to tumorigenesis, tumor progression, and therapeutic resistance to DNA-damaging anti-tumor agents. Rad51 recombinase is a critical effector of homologous recombination, which is an essential DNA repair mechanism for double-strand breaks. Rad51 has been found to be upregulated in many malignant solid tumors, and is correlated with poor prognosis. In multiple tumor types, Rad51 is critical for tumor metabolism, metastasis and drug resistance. Herein, we initially introduced the structure, expression pattern of Rad51 and key Rad51 mediators involved in homologous recombination. Additionally, we primarily discussed the role of Rad51 in tumor metabolism, metastasis, resistance to chemotherapeutic agents and poly-ADP ribose polymerase inhibitors.

show abstract

Basal expression of RAD51 foci predicts olaparib response in patient-derived ovarian cancer xenografts

Cited by 26 publications

References 46 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

Onvansertib and paclitaxel combined in platinum-resistant ovarian carcinomas

The Emerging Roles of Rad51 in Cancer and Its Potential as a Therapeutic Target

Contact Info

Product

Resources

About