Chemosensitive relapse in small cell lung cancer proceeds through an EZH2-SLFN11 axis Journal Article


Authors: 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.
Article Title: Chemosensitive relapse in small cell lung cancer proceeds through an EZH2-SLFN11 axis
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. © 2017 Elsevier Inc.
Keywords: cisplatin; etoposide; small cell lung cancer; ezh2; acquired resistance; patient-derived xenograft; epz011989; slfn11; twist1
Journal Title: Cancer Cell
Volume: 31
Issue: 2
ISSN: 1535-6108
Publisher: Cell Press  
Date Published: 2017-02-13
Start Page: 286
End Page: 299
Language: English
DOI: 10.1016/j.ccell.2017.01.006
PROVIDER: scopus
PMCID: PMC5313262
PUBMED: 28196596
DOI/URL:
Notes: Article -- Export Date: 2 March 2017 -- Source: Scopus
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MSK Authors
  1. Natasha Rekhtman
    210 Rekhtman
  2. Benjamin H Lok
    53 Lok
  3. Charles Rudin
    162 Rudin
  4. John Thomas Poirier
    55 Poirier
  5. Linde Anne Miles
    6 Miles
  6. Eric Edison Gardner
    13 Gardner
  7. Inna   Khodos
    6 Khodos
  8. Ai   Ni
    48 Ni
  9. Paige Krystin Arnold
    2 Arnold