Abstract IA7: Chromosome instability and synthetic lethality in yeast and cancer

Abstract

Abstract Genes that maintain chromosome stability (CIN genes) are conserved in eukaryotes and are often somatically mutated in cancer. We have been identifying synthetic lethal partner genes, in yeast synthetic lethal (SL) interaction networks, that are highly connected with sets of CIN genes somatically mutated in cancer. This identifies hub proteins and processes that are candidate targets for synthetic lethal killing of cancer cells with defined CIN gene somatic mutations. One hub process in these networks is DNA replication. The protein product of FEN1 (encoding flap endonuclease) was used as a target for small-molecule inhibitor screening using a fluorescence-based assay for enzyme activity. Inhibitors of FEN1 activity in vitro were shown to selectively inhibit the proliferation of cultured cancer cells carrying inactivating mutations in CDC4, or knockdown or inhibition of MRE11A, two genes frequently mutated in a variety of cancers. Analysis of synthetic lethal interactions with cohesin gene mutations, a class of somatic mutation found in several tumor types, found that cohesin mutants require the function of genes that mediate replication fork progression. PARP1 has roles in the DNA damage response but also the restart of stalled replication forks. We found that cohesin mutants exhibited synthetic lethal interactions with PARP mutants in C. elegans, and demonstrated that this interaction is conserved in human cells by showing that PARP inhibitors reduce the viability of cultured human cells depleted for cohesin components. Solomon, Waldman et al (Science 333:1039-43, 2011) have shown that the cohesin subunit gene, STAG2, is recurrently mutated in glioblastoma, Ewing's sarcoma, and melanoma tumors. Using matched glioblastoma cell lines containing either a truncated STAG2 or wild-type STAG2 knock-in, we found that STAG2 mutants undergo significantly decreased proliferation in the presence of PARP inhibition, suggesting that PARP inhibitors may be effective in treating cancers carrying somatic mutations in cohesin genes. Citation Format: Philip Hieter, Melanie Bailey, Nigel O'Neil, Derek van Pel, Peter Stirling. Chromosome instability and synthetic lethality in yeast and cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr IA7.