Abstract 4693: The putative DNA/RNA Helicase Schlafen-11 sensitizes cancer cells to topoisomerase I inhibitors
Authors: Zoppoli Gabriele , Regairaz Marie , Leo Elisabetta , Reinhold William C. , Pommier Yves 
Published: August 2012

It is critically important to identify the molecular determinants and predictive molecular markers of cancer sensitivity to topoisomerase I (TOP1) inhibitors to personalize treatments and rationalize combination therapies. The NCI Anticancer Tumor Cell Line panel (NCI-60) encompasses 60 cancer cell lines from nine different tissues of origin, which have been tested since the 1980s for more than 400,000 compounds of natural and synthetic origin. Moreover, the NCI-60 have been extensively characterized for gene expression and miRNA with six different array platforms, copy number variation by aCGH, and are currently being sequenced for the entire exome and transcriptome at the NCI. To identify genes that, at the expression level, could predict the in vitro cytotoxicity profiles of TOP1 inhibitors in the NCI-60, we correlated the expression profile of more than 17,000 genes, finding 294 genes that correlated with camptothecin (CPT), 217 with topotecan, 699 with irinotecan, and 734 with a new non-CPT indenoisoquinoline derivative in clinical trial NSC724998, at a P &lt; 0.01 (Spearman's rank correlation test, two-tailed, uncorrected). By intersecting these four sets, we identified 42 common genes, 23 of which were positively and 19 negatively correlating with the four TOP1 inhibitors. A single gene, SLFN11 showed a Spearman's ≤ &gt; + 0.613 with all the four compounds (uncorrected P &lt; 2.5 x 10−7, two-tailed), as well as with several other CPT analogs. To test the causal relationship between SLFN11 expression and sensitivity to TOP1 inhibitors in cancer cell lines, we silenced SLFN11 expression in two different human lines: DU-145 (prostate) and HOP-62 (non-small cell lung cancer), both expressing SLFN11 and showing high sensitivities to TOP1 inhibitors. In both cell lines, siRNA-mediated silencing of SLFN11 induced a remarkable resistance to CPT. While SLFN11 expression was strongly positively correlated to the response to TOP1 inhibitors and other DNA damaging agents in the NCI-60, it did not correlate with other classes of chemotherapeutic agents such as microtubule-targeting compounds or kinase inhibitors. Accordingly, SLFN11 siRNA-induced depletion did not affect the cellular response to paclitaxel or the apoptosis inducer staurosporine. In conclusion, the identification of SLFN11 modulating effects towards in vitro response to TOP1 inhibitors lays the ground for the study of a previously unexplored player of cancer cell response to that class of agents. Moreover, SLFN11 expression could be tested in human tumor samples as a biomarker in response prediction to TOP1 inhibitor-based chemotherapeutical regimens, such as those used in colorectal and ovarian cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4693. doi:1538-7445.AM2012-4693