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 |
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
Related MSK Work