Abstract 3921: Fen-1 inhibition: Synthetic lethal opportunities in Rad54B-defective tumours, ALT-pathway backgrounds and beyond

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Flap endonuclease-1 (FEN-1) is a 5′-3’ exonuclease and a 5’ flap endonuclease, required for Okazaki fragment processing as well as for long-patch base-excision repair (BER) and non-homologous end-joining (NHEJ). From datamining AstraZeneca's extensive GeAZR database, as well as from Oncomine searches, FEN-1 is over-expressed in lung, ovary, bladder, gastric and 5-FU-resistant cancer cell lines. Screens carried out in yeast (Saccharomyces Genome Database) reveal over 250 genes as being synthetic lethal with the yeast homolog Rad27. Recently using human model systems, FEN-1 suppression was confirmed to be synthetic lethal with the human homolog of yeast Rad54B in Rad54B-deficient colorectal cancer (CRC) cell lines. FEN-1 suppression has also been reported to selectively sensitise hTERT-deficient ALT (Alternative pathway for lengthening telomeres) cell lines. To gain in-house confidence in this synthetic lethal target validation approach, we have used molecular tools to test synthetic lethal opportunities in matched Rad54B-RNAi-suppressed cell lines and confirm selective sensitisation. We also intend to explore further synthetic lethal backgrounds as well as in combination with chemotherapeutic standards of care. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3921. doi:10.1158/1538-7445.AM2011-3921