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

• Published in: British journal of cancer Vol. 126; no. 1; pp. 120 - 128
• Main Authors: Guffanti, F., Alvisi, M F, Anastasia, A., Ricci, F., Chiappa, M., Llop-Guevara, A., Serra, V., Fruscio, R., Degasperi, A., Nik-Zainal, S., Bani, M R, Lupia, M., Giavazzi, R., Rulli, E., Damia, G.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2022; Nature Publishing Group
• Subjects: 631/67/1517/1709; 631/67/1857; Antineoplastic Agents - pharmacology; Biomarkers; Biomedical and Life Sciences; Biomedicine; BRCA1 protein; BRCA1 Protein - genetics; BRCA2 Protein - genetics; Cancer Research; Cell Line, Tumor; Cisplatin - pharmacology; DNA methylation; DNA repair; Drug Resistance; Epidemiology; Female; Geminin; Gene expression; Homologous Recombination; Humans; Immunofluorescence; Molecular Medicine; Oncology; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Paraffin; Patients; Phthalazines - pharmacology; Piperazines - pharmacology; Platinum; Rad51 Recombinase - metabolism; Ribose; Tumors; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-021-01609-1

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.