Chemosensitive Relapse in Small Cell Lung Cancer Proceeds through an EZH2-SLFN11 Axis Academic Article uri icon

Overview

MeSH Major

  • Enhancer of Zeste Homolog 2 Protein
  • Lung Neoplasms
  • Nuclear Proteins
  • Small Cell Lung Carcinoma

abstract

  • 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.

publication date

  • February 13, 2017

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC5313262

Digital Object Identifier (DOI)

  • 10.1016/j.ccell.2017.01.006

PubMed ID

  • 28196596

Additional Document Info

start page

  • 286

end page

  • 299

volume

  • 31

number

  • 2