| Literature DB >> 28196596 |
Eric E Gardner1, Benjamin H Lok2, Valentina E Schneeberger3, Patrice Desmeules4, Linde A Miles3, Paige K Arnold5, Andy Ni6, Inna Khodos7, Elisa de Stanchina8, Thuyen Nguyen9, Julien Sage9, John E Campbell10, Scott Ribich10, Natasha Rekhtman4, Afshin Dowlati11, Pierre P Massion12, Charles M Rudin13, John T Poirier14.
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.Entities:
Keywords: EPZ011989; EZH2; SLFN11; TWIST1; acquired resistance; cisplatin; etoposide; patient-derived xenograft; small cell lung cancer
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Year: 2017 PMID： 28196596 PMCID： PMC5313262 DOI： 10.1016/j.ccell.2017.01.006
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743