Overcoming Resistance to DNA-Targeted Agents by Epigenetic Activation of Schlafen 11 (<i>SLFN11)</i> Expression with Class I Histone Deacetylase Inhibitors.

Abstract

<b>Purpose:</b> Schlafen 11 (SLFN11), a putative DNA/RNA helicase is a dominant genomic determinant of response to DNA-damaging agents and is frequently not expressed in cancer cells. Whether histone deacetylase (HDAC) inhibitors can be used to release <i>SLFN11</i> and sensitize SLFN11-inactivated cancers to DNA-targeted agents is tested here.<b>Experimental Design:</b><i>SLFN11</i> expression was examined in The Cancer Genome Atlas (TCGA), in cancer cell line databases and in patients treated with romidepsin. Isogenic cells overexpressing or genetically inactivated for SLFN11 were used to investigate the effect of HDAC inhibitors on <i>SLFN11</i> expression and sensitivity to DNA-damaging agents.<b>Results:</b><i>SLFN11</i> expression is suppressed in a broad fraction of common cancers and cancer cell lines. In cancer cells not expressing <i>SLFN11</i>, transfection of <i>SLFN11</i> sensitized the cells to camptothecin, topotecan, hydroxyurea, and cisplatin but not to paclitaxel. <i>SLFN11</i> mRNA and protein levels were strongly induced by class I (romidepsin, entinostat), but not class II (roclinostat) HDAC inhibitors in a broad panel of cancer cells. <i>SLFN11</i> expression was also enhanced in peripheral blood mononuclear cells of patients with circulating cutaneous T-cell lymphoma treated with romidepsin. Consistent with the epigenetic regulation of <i>SLFN11</i>, camptothecin and class I HDAC inhibitors were synergistic in many of the cell lines tested.<b>Conclusions:</b> This study reports the prevalent epigenetic regulation of <i>SLFN11</i> and the dominant stimulatory effect of HDAC inhibitors on <i>SLFN11</i> expression. Our results provide a rationale for combining class I HDAC inhibitors and DNA-damaging agents to overcome epigenetic inactivation of <i>SLFN11</i>-mediated resistance to DNA-targeted agents. <i>Clin Cancer Res; 24(8); 1944-53. ©2018 AACR</i>.