Chemosensitive Relapse in Small Cell Lung Cancer Proceeds through an EZH2-SLFN11 Axis

Small cell lung cancer is initially highly responsive to cisplatin and etoposide but in almost every case becomes rapidly chemoresistant, leading to death within 1 year. We modeled acquired chemoresistance in vivo using a series of patient-derived xenografts to generate paired chemosensitive and chemoresistant cancers. Multiple chemoresistant models demonstrated suppression of SLFN11, a factor implicated in DNA-damage repair deficiency. In vivo silencing of SLFN11 was associated with marked deposition of H3K27me3, a histone modification placed by EZH2, within the gene body of SLFN11, inducing local chromatin condensation and gene silencing. Inclusion of an EZH2 inhibitor with standard cytotoxic therapies prevented emergence of acquired resistance and augmented chemotherapeutic efficacy in both chemosensitive and chemoresistant models of small cell lung cancer. [Display omitted] •EZH2 drives acquired resistance to chemotherapy in small cell lung cancer (SCLC)•DNA damage induces genome-wide EZH2 activity and H3K27me3 deposition in SCLC•SLFN11 is an EZH2 target gene in SCLC•Combining an EZH2 inhibitor with standard of care controls SCLC in vivo By generating paired chemonaive and chemoresistant small cell lung cancer (SCLC) patient-derived xenograft models, Gardner et al. find that EZH2 promotes chemoresistance by epigenetically silencing SLFN11. EZH2 inhibition prevents acquisition of chemoresistance and improves chemotherapeutic efficacy in SCLC.