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

doi:10.1016/j.ccell.2017.01.006

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

School of Medicine

Research output: Contribution to journal › Article › peer-review

167 Scopus citations

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 language	English (US)
Pages (from-to)	286-299
Number of pages	14
Journal	Cancer Cell
Volume	31
Issue number	2
DOIs	https://doi.org/10.1016/j.ccell.2017.01.006
State	Published - 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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10.1016/j.ccell.2017.01.006

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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

Gardner, EE, Lok, BH, Schneeberger, VE, Desmeules, P, Miles, LA, Arnold, PK, Ni, A, Khodos, I, de Stanchina, E, Nguyen, T, Sage, J, Campbell, JE, Ribich, S, Rekhtman, N, Dowlati, A, Massion, PP, Rudin, CM & Poirier, JT 2017, 'Chemosensitive Relapse in Small Cell Lung Cancer Proceeds through an EZH2-SLFN11 Axis', Cancer Cell, vol. 31, no. 2, pp. 286-299. https://doi.org/10.1016/j.ccell.2017.01.006

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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.",

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AU - Khodos, Inna

AU - de Stanchina, Elisa

AU - Nguyen, Thuyen

AU - Sage, Julien

AU - Campbell, John E.

AU - Ribich, Scott

AU - Rekhtman, Natasha

AU - Dowlati, Afshin

AU - Massion, Pierre P.

AU - Rudin, Charles M.

AU - Poirier, John T.

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N2 - 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.

AB - 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.

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

Abstract

Keywords

ASJC Scopus subject areas

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