Abstract
Platinum resistance is an unmet medical need in ovarian carcinoma. Molecular biomarkers to predict the response to platinum-based therapy could allow patient stratification and alternative therapeutic strategies early in clinical management. Sensitivity and resistance to platinum therapy are partially determined by the tumor’s intrinsic DNA repair activities, including nucleotide excision repair (NER) and base excision repair (BER). We investigated the role of the NER proteins—ERCC1, XPF, ERCC1/XPF complex—and of the BER protein DNA polymerase β, as possible biomarkers of cisplatin (DDP) response in a platform of recently established patient-derived ovarian carcinoma xenografts (OC-PDXs). ERCC1 and DNA polymerase β protein expressions were measured by immunohistochemistry, the ERCC1/XPF foci number was detected by proximity ligation assay (PLA) and their mRNA levels by real-time PCR. We then correlated the proteins, gene expression and ERCC1/XPF complexes with OC-PDXs’ response to platinum. To the best of our knowledge, this is the first investigation of the role of the ERCC1/XPF complex, detected by PLA, in relation to the response to DDP in ovarian carcinoma. None of the proteins in the BER and NER pathways studied predicted platinum activity in this panel of OC-PDXs, nor did the ERCC1/XPF foci number. These results were partially explained by the experimental evidence that the ERCC1/XPF complex increases after DDP treatment and this possibly better associates with the cancer cells’ abilities to activate the NER pathway to repair platinum-induced damage than its basal level. Our findings highlight the need for DNA functional assays to predict the response to platinum-based therapy.
Highlights
Platinum-based therapy is one of the main effective treatments for different solid tumors [1].The platinum-taxol doublet is first-line therapy for ovarian carcinoma with a high response rate
Given the importance of DNA repair in DDP cytotoxicity and having available an ovarian carcinoma PDX platform which, as a whole, represents the complexity of human ovarian carcinoma and has been pharmacologically characterized in vivo for the response to platinum-based therapy [31], we investigated the roles of the excision repair cross-complementation group 1 (ERCC1)/XerodermaPigmentosum complementation group F (XPF) complex and DNA pol β as possible biomarkers of DDP response
None of the proteins involved in the base excision repair (BER) and nucleotide excision repair (NER) pathways studied here predicted platinum activity in a panel of ovarian cancer xenografts
Summary
Platinum-based therapy is one of the main effective treatments for different solid tumors [1].The platinum-taxol doublet is first-line therapy for ovarian carcinoma with a high response rate (more than 80%). Most patients relapse, with a resistant disease [2]. Understanding the mechanisms of platinum resistance is of paramount importance, as knowing a priori, that a tumor will probably not respond would help direct patients to an alternative therapy. Cisplatin (DDP) and carboplatin are used in the management of ovarian carcinoma and their activity is mainly due to the formation of DNA monoadducts, adducts between adjacent purines (DNA intra-strand crosslinks) and between bases on opposite strands (DNA inter-strand crosslinks, ICLs). These DNA lesions, the latter, are cytotoxic, as they interfere with transcription and replication, causing cell cycle arrest and inducing apoptosis [3,4]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
