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

Abstract

SUMMARY Small cell lung cancer is initially highly responsive to cisplatin and etoposide but in almost every case becomes rapidly chemoresistant, leading to death within one 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.

Small cell lung cancer tumors and preclinical models display heterogeneity of neuroendocrine phenotypes

“…These included NFIB (74), SLFN11 (75,76), BCL2 (28), SOX2 and EZH2 (70,77). Figure 9 is a summary of the main differences between the NE high and low subtypes.…”

Targeting DNA damage in SCLC

“…SLFN11 is actively recruited to sites of DNA damage, inhibiting HR respectively) [54] and activating a cellular replication-stress response [55,56]. SLFN11 suppression has been associated with chemoresistance in SCLC models [57] and identified as a biomarker of PARP inhibitor response in SCLC PDX [44]. Circulating tumour cell enumeration was undertaken at baseline and after 1 cycle of chemotherapy.…”

Identification of candidate responders for anti-PD-L1/PD-1 immunotherapy, Rova-T therapy, or EZH2 inhibitory therapy in small-cell lung cancer

“…A recent clinical trial demonstrated that rovalpituzumab tesirine (Rova-T), a DLL3-targeted antibody-drug conjugate, exhibited marked antitumor activity and durability in recurrent or refractory SCLC (20). EZH2 is also highly expressed in SCLC, and its inhibition by EZH2 inhibitor enhances the effectiveness of current standard chemotherapy (21). Higher expression of DLL3 and EZH2 in SCLC was associated with a higher rate of response to Rova-T and EZH2 inhibitor, respectively; thus, DLL3 and EZH2 expression may be a candidate predictive biomarker for SCLC treatment.…”