Abstract 4449: Synthetic lethality between CSTF2 and CSTF2T in lung adenocarcinoma and melanoma cell lines

Genomic instability is a hallmark of cancer and can result in the deletion of genes with no apparent or as yet unknown relevance to tumor survival and proliferation. Although the deletion of such genes may be tolerated due to functional compensation it, however, entails a cancer cell specific vulnerability as the tumor cell relies on the function of compensating redundant genes. Recurrent deletions of cleavage stimulation factor subunit 2 Tau (CSTF2T) have been observed in several tumor samples (TCGA). During meiosis CSTF2, a paralogue of CSTF2T, which resides on the X-chromosome, is transcriptionally silenced and the zygote depends on the activity of CSTF2T. As a result, CSTF2T knockout mice exhibit male sterility which corroborates that CSTF2 and CSTF2T form a functionally redundant pair of genes with an essential function (Dass et al. 2007). With the aim to apply these findings to tumor biology, we therefore tested whether tumor cells with homozygous CSTF2T deletions depend on CSTF2 using CRISPR-based growth competition assays and confirmed this concept in lung adenocarcinoma and melanoma cell line models. Our data establish synthetic lethality between CSTF2 and CSTF2T and suggest inhibition of CSTF2 in CSTF2T deficient tumors as a new therapeutic concept. Citation Format: Johannes Popow, Corinna Wieshofer, Andreas Schlattl, Simon Woehrle, Ralph Neumuller, Mark P. Petronczki, Jark Boettcher, Manfred Koegl, Mark Pearson. Synthetic lethality between CSTF2 and CSTF2T in lung adenocarcinoma and melanoma cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4449.