Abstract SLFN11 expression correlates with sensitivity of tumors to topoisomerase and DNA-targeting drugs and consequently with prognosis. Regulation of SLFN11 by ETS factors opens new avenues to treatment optimization, maximizing antitumor activity and minimizing adverse side effects. Interrogating drug-induced gene expression signatures for SLFN11 modulations may affect the design of therapeutic regimens. Clin Cancer Res; 21(18); 4033–4. ©2015 AACR. See related article by Tang et al., p. 4184