Abstract PL05-01: ERCC1 alternative readouts

Abstract

Abstract Platinum-based compounds, including cisplatin and oxaliplatin, trigger cell death by distorting the helix structure and subsequently affecting DNA replication and transcription. The therapeutic efficacy of platinum-based chemotherapy varies among patients and only a portion of them have real benefits. Precision medicine searches for the optimal therapy for each patient. The proteins involved in DNA repair are thus potential biomarkers to select patients more prone to respond to platinum-based chemotherapy. The ERCC1 (excision repair cross-complementation group 1) protein is essential in nucleotide excision repair (NER) and other repair pathways involved in the repair of platinum-induced DNA damages. ERCC1 with its partner XPF (xeroderma pigmentosum complementation group F) form a structure-specific endonuclease that is responsible for 5' incision during DNA repair. ERCC1 has been reported to be a prognostic and predictive biomarker for cisplatin treatments in various cancers. Many studies have shown that the ERCC1 status, including ERCC1 polymorphisms, ERCC1 RNA expression and ERCC1 protein expression, are associated with platinum-based therapy efficacy. However, this correlation between ERCC1 status and the clinical outcome has not always reached a consensus, probably due to inadequate methods to determine ERCC1 expression and unreliability of the current commercial ERCC1 antibodies. Alternative splicing leads to several isoforms of ERCC1. We have reported that only ERCC1-202 mediates highly efficient removal of platinum-GG intrastrand adducts and should therefore be considered as the only functional isoform. Putative roles of the other isoforms remain unknown. The expression of ERCC1 is mostly determined by qRT-PCR or IHC. However, these two methods are not able to discriminate the functional ERCC1-202 isoform from other isoforms. We will present the design of a tailor-made antibody directed against the interacting complex ERCC1/XPF. This new ERCC1/XPF heterodimer-specific antibody permits the detection of the functional ERCC1-202 isoform when it is used in combination with other antibodies in proximity ligation assays (PLA). The applicability of this alternative read out for ERCC1 expression on clinical samples will be discussed. Citation Format: Mei-Shiue Kuo, Ken A. Olaussen, Jean-Charles Soria. ERCC1 alternative readouts. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr PL05-01.