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

Eric E. Gardner, Benjamin H. Lok, Valentina E. Schneeberger, Patrice Desmeules, Linde A. Miles, Paige K. Arnold, Andy Ni, Inna Khodos, Elisa de Stanchina, Thuyen Nguyen, Julien Sage, John E. Campbell, Scott Ribich, Natasha Rekhtman, Afshin Dowlati, Pierre P. Massion, Charles M. Rudin, John T. Poirier

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)286-299
Number of pages14
JournalCancer Cell
Volume31
Issue number2
DOIs
StatePublished - Feb 13 2017

Keywords

  • acquired resistance
  • cisplatin
  • EPZ011989
  • etoposide
  • EZH2
  • patient-derived xenograft
  • SLFN11
  • small cell lung cancer
  • TWIST1

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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  • Cite this

    Gardner, E. E., Lok, B. H., Schneeberger, V. E., Desmeules, P., Miles, L. A., Arnold, P. K., Ni, A., Khodos, I., de Stanchina, E., Nguyen, T., Sage, J., Campbell, J. E., Ribich, S., Rekhtman, N., Dowlati, A., Massion, P. P., Rudin, C. M., & Poirier, J. T. (2017). Chemosensitive Relapse in Small Cell Lung Cancer Proceeds through an EZH2-SLFN11 Axis. Cancer Cell, 31(2), 286-299. https://doi.org/10.1016/j.ccell.2017.01.006