EZH2 Inhibition May Prevent Chemoresistance in SCLC

Patients with small cell lung cancer (SCLC) are initially responsive to chemotherapy, but chemoresistance develops rapidly. The molecular mechanisms underlying the development of resistance are not well understood, prompting Gardner and colleagues to model acquired resistance using ten paired chemosensitive and chemoresistant SCLC patient-derived xenografts (PDX). Whole-exome sequencing of the paired PDXs showed that key genetic alterations were maintained through the acquisition of chemoresistance, suggesting that epigenetic mechanisms may be responsible for acquired chemoresistance. Gene expression profiles were largely similar between chemosensitive and chemoresistant tumors. However, a minority of genes exhibited altered expression, including SLFN11, which contributes to DNA-damage repair deficiencies and was significantly downregulated in 4 of 10 PDX models. SLFN11 expression was reduced in SCLC cell lines and tumor samples from previously treated patients, indicating that SLFN11 may be silenced by chemotherapy. The histone methyltransferase EZH2 is highly expressed in SCLC, and inhibition of EZH2 with EPZ011989 (EPZ) increased SLFN11 expression and restored sensitivity to topoisomerase inhibitors in cell lines and ex vivo cultures from the chemoresistant PDXs. Further, overexpression of SLFN11 was sufficient to sensitize cells to topotecan, implicating SLFN11 as a critical factor in SCLC sensitivity to DNA-damaging agents. Chemotherapy caused a global increase in H3K27me3 and a decrease in H3K27ac in chemoresistant cells. EZH2 and H3K27me3 were highly concentrated at the transcription start site of SLFN11, and the acquisition of chemoresistance was accompanied by H3K27me3 spreading to the gene body and a near-complete loss of H3K27ac. EPZ treatment removed H3K27me3 throughout the SLFN11 gene body, promoting its reexpression. EPZ was well tolerated in mice and slowed tumor growth in PDX models that acquired resistance by SLFN11 silencing. Further, in combination with chemotherapy, EPZ induced tumor regression and prevented chemoresistance. The finding that EZH2 promotes chemoresistance through SLFN11 silencing suggests that EZH2 inhibition may prevent chemoresistance in patients with SCLC and enhance the efficacy of chemotherapy.

Gardner EE, Lok BH, Schneeberger VE, Desmeules P, Miles LA, Arnold PK, et al. Chemosensitive relapse in small cell lung cancer proceeds through an EZH2-SLFN11 axis. Cancer Cell 2017;31:286–99.

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