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Cellular and Molecular Biology

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

British Journal of Cancer volume 126, pages 120–128 (2022)Cite this article

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A Correction to this article was published on 16 February 2023

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Abstract

Background

The search for biomarkers to evaluate ovarian cancer (OC) homologous recombination (HR) function and predict the response to therapy is an urgent clinical need to improve the selection of patients who could benefit from platinum- and olaparib (poly-ADP ribose polymerase inhibitors, PARPi)-based therapies.

Methods

We used a large collection of OC patient-derived xenografts (PDXs) (n = 47) and evaluated their HR status based on BRCA1/2 mutations, BRCA1 promoter methylation and the HRDetect score. RAD51 foci were quantified in formalin-fixed, paraffin-embedded untreated tumour specimens by immunofluorescence and the messenger RNA expression of 21 DNA repair genes by real-time PCR.

Results

Tumour HR deficiency predicted both platinum and olaparib responses. The basal level of RAD51 foci evaluated in geminin-positive/replicating cells strongly inversely correlated with olaparib response (p = 0.011); in particular, the lower the foci score, the greater the sensitivity to olaparib, while low RAD51 foci score seems to associate with platinum activity.

Conclusions

The basal RAD51 foci score is a candidate predictive biomarker of olaparib response in OC patients as it can be easily translatable in a clinical setting. Moreover, the findings corroborate the importance of OC-PDXs as a reliable tool to identify and validate biomarkers of response to therapy.

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Fig. 1: Responses to cisplatin and olaparib and HR/BRCA profile of the subcutaneously (s.c.) transplanted OC-PDXs.
Fig. 2: Responses to cisplatin and olaparib and HR/BRCA profile of the intraperitoneally (i.p.) transplanted OC-PDXs.
Fig. 3: Percentages of cells positive to RAD51 foci in OC-PDXs and their response to olaparib.
Fig. 4: RAD51 foci in geminin-positive cells and responses to cisplatin and olaparib in the OC-PDXs.

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Data availability

All data supporting the conclusions of this study have been included within the article and the Supplemental data.

Materials availability

All materials supporting the conclusions of this study have been included within the article and the Supplemental data.

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Acknowledgements

We gratefully acknowledged the Italian Association for Cancer Research (AIRC) and 3M Foundation for financial support and to “Pandora”, the ovarian cancer tissue collection (Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Department of Oncology). We also acknowledge Judith Bagott for editing the manuscript.

Funding

The research leading to these results received funding from AIRC (IG ID19797 project—PI Damia Giovanna; IG ID23520—PI Giavazzi Raffaella). AL-G received salary support from the Spanish Association against Cancer (Asociación Española Contra el Cáncer, AECC, INVES20095LLOP) and a grant from “la Caixa” Foundation and European Institute of Innovation and Technology/Horizon 2020 (CaixaImpulse, LCF/TR/CC19/52470003), during the conduct of the study. VS reports personal support from Instituto de Salud Carlos III (ISCIII, CPII19/00033).

Author information

Authors and Affiliations

  1. Laboratory of Molecular Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy

    F. Guffanti, F. Ricci, M. Chiappa & G. Damia

  2. Laboratory of Methodology for Clinical Research, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy

    M F Alvisi & E. Rulli

  3. Laboratory of Cancer Metastasis Therapeutics, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy

    A. Anastasia, M R Bani & R. Giavazzi

  4. Experimental Therapeutics Group, Vall d’Hebron Institute of Oncology, Barcelona, Spain

    A. Llop-Guevara & V. Serra

  5. Clinic of Obstetrics and Gynecology, Department of Medicine and Surgery, San Gerardo Hospital, University of Milan Bicocca, Monza, Italy

    R. Fruscio

  6. MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Box 197, Cambridge Biomedical Campus, Cambridge, CB2 0XZ, UK

    A. Degasperi & S. Nik-Zainal

  7. Academic Laboratory of Medical Genetics, Lv 6 Addenbrooke’s Treatment Centre, Addenbrooke’s Hospital, Box 238, Cambridge, CB2 0QQ, UK

    A. Degasperi & S. Nik-Zainal

  8. Unit of Gynecological Oncology Research, IEO, European Institute of Oncology IRCCS, Milan, Italy

    M. Lupia

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Contributions

Conceptualisation and study design: FG, MFA, ER and GD; development of methodology: FG, MC, FR, AL-G, DA and GD; data acquisition: FG, AA, MC, FR, AL-G, DA, VS, SN-Z, RF, ML and MRB; formal and statistical analysis: FG, MFA, GD, ER, DA, SN-Z, AL-G and MRB; manuscript writing, review and revision: FG, GD, AL-G, MFA, ER, VS, DA, MRB and RG; study supervision: GD. All authors read and critically revised the manuscript for intellectual content and approved the final manuscript.

Corresponding author

Correspondence to G. Damia.

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Competing interests

VS reports grants from AstraZeneca, Tesaro and personal fees from Abbvie, outside the submitted work. In addition, AL-G and VS have a patent WO2019122411A1 pending. The other authors declare no competing interests.

Ethics approval and consent to participate

All animal experiments were approved by the Ethical Committee of the Mario Negri Institute for Pharmacological Research IRCCS and the Italian Ministry of Health (approval numbers 510-2016 and 296/2018-PR).

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The original online version of this article was revised: The original version of this article contained an affiliation error. Affiliation 8 affiliation states: “Unit of Gynecological Oncology Research, European Institute of Oncology, Milan, Italy” and needs to be changed to: “Unit of Gynecological Oncology Research, IEO, European Institute of Oncology IRCCS, Milan, Italy”.

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Guffanti, F., Alvisi, M.F., Anastasia, A. et al. Basal expression of RAD51 foci predicts olaparib response in patient-derived ovarian cancer xenografts. Br J Cancer 126, 120–128 (2022). https://doi.org/10.1038/s41416-021-01609-1

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