Pierre Massion
Faculty Member
Last active: 1/11/2018

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

Gardner EE, Lok BH, Schneeberger VE, Desmeules P, Miles LA, Arnold PK, Ni A, Khodos I, de Stanchina E, Nguyen T, Sage J, Campbell JE, Ribich S, Rekhtman N, Dowlati A, Massion PP, Rudin CM, Poirier JT
Cancer Cell. 2017 31 (2): 286-299

PMID: 28196596 · PMCID: PMC5313262 · DOI:10.1016/j.ccell.2017.01.006

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.

Copyright © 2017 Elsevier Inc. All rights reserved.

MeSH Terms (9)

Animals Drug Resistance, Neoplasm Enhancer of Zeste Homolog 2 Protein Humans Lung Neoplasms Mice Nuclear Proteins Small Cell Lung Carcinoma Twist-Related Protein 1

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