Platinum sensitivity and DNA repair in a recently established panel of patient-derived ovarian carcinoma xenografts

// Federica Guffanti 1 , Maddalena Fratelli 2 , Monica Ganzinelli 3 , Marco Bolis 2 , Francesca Ricci 1 , Francesca Bizzaro 1 , Rosaria Chilà 1 , Federica Paola Sina 4 , Robert Fruscio 4 , Michela Lupia 5 , Ugo Cavallaro 5 , Maria Rosa Cappelletti 6 , Daniele Generali 6, 7 , Raffaella Giavazzi 1 and Giovanna Damia 1 1 Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy 2 Department of Biochemistry, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy 3 Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 4 Clinic of Obstetrics and Gynecology, San Gerardo Hospital, University of Milan-Bicocca, Department of Medicine and Surgery, Milan, Italy 5 Unit of Gynecological Oncology Research, European Institute of Oncology, Milan, Italy 6 Breast Cancer Unit and Translational Research Unit, ASST Cremona, Cremona, Italy 7 Department of Medical, Surgery and Health Sciences, University of Trieste, Trieste, Italy Correspondence to: Giovanna Damia, email: giovanna.damia@marionegri.it Keywords: ovarian cancer; patients-derived xenografts; cisplatin; drug resistance; DNA repair Received: January 29, 2018 Accepted: April 05, 2018 Published: May 15, 2018 ABSTRACT A xenobank of patient-derived (PDX) ovarian tumor samples has been established consisting of tumors with different sensitivity to cisplatin (DDP), from very responsive to resistant. As the DNA repair pathway is an important driver in tumor response to DDP, we analyzed the mRNA expression of 20 genes involved in the nucleotide excision repair, fanconi anemia, homologous recombination, base excision repair, mismatch repair and translesion repair pathways and the methylation patterns of some of these genes. We also investigated the correlation with the response to platinum-based therapy. The mRNA levels of the selected genes were evaluated by Real Time-PCR (RT-PCR) with ad hoc validated primers and gene promoter methylation by pyrosequencing. All the DNA repair genes were variably expressed in all 42 PDX samples analyzed, with no particular histotype-specific pattern of expression. In high-grade serous/endometrioid PDXs, the CDK12 mRNA expression levels positively correlated with the expression of TP53BP1, PALB2, XPF and POLB. High-grade serous/endometrioid PDXs with TP53 mutations had significantly higher levels of POLQ, FANCD2, RAD51 and POLB than high-grade TP53 wild type PDXs. The mRNA levels of CDK12, PALB2 and XPF inversely associated with the in vivo DDP antitumor activity; higher CDK12 mRNA levels were associated with a higher recurrence rate in ovarian patients with low residual tumor. These data support the important role of CDK12 in the response to a platinum based therapy in ovarian patients.