Oncotarget

Priority Research Papers:

Evaluation of azacitidine and entinostat as sensitization agents to cytotoxic chemotherapy in preclinical models of non-small cell lung cancer

Frank P. Vendetti _, Michael Topper, Peng Huang, Irina Dobromilskaya, Hariharan Easwaran, John Wrangle, Stephen B. Baylin, J. T. Poirier, Charles M. Rudin

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Abstract

Frank P. Vendetti1, Michael Topper1, Peng Huang1, Irina Dobromilskaya1, Hariharan Easwaran1, John Wrangle1, Stephen B. Baylin1, J. T. Poirier2, Charles M. Rudin2

1The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD

2Memorial Sloan Kettering Cancer Center, NY 10065, New York

Correspondence to:

Charles M. Rudin, e-mail: rudinc@mskcc.org

Keywords: epigenetic, azacitidine, entinostat, priming, chemosensitivity, non-small cell lung cancer (NSCLC)

Received: July 25, 2014     Accepted: November 04, 2014     Published: November 25, 2014

ABSTRACT

Recent clinical data in lung cancer suggests that epigenetically targeted therapy may selectively enhance chemotherapeutic sensitivity. There have been few if any studies rigorously evaluating this hypothesized priming effect. Here we describe a series of investigations testing whether epigenetic priming with azacitidine and entinostat increases sensitivity of NSCLC to cytotoxic agents.

We noted no differences in chemosensitivity following treatment with epigenetic therapy in in vitro assays of viability and colony growth. Using cell line and patientderived xenograft (PDX) models, we also observed no change in responsiveness to cisplatin in vivo. In select models, we noted differential responses to irinotecan treatment in vivo. In vitro epigenetic therapy prior to tumor implantation abrogated response of H460 xenografts to irinotecan. Conversely, in vitro epigenetic therapy appeared to sensitize A549 xenografts (tumor growth inhibition 51%, vs. 22% in mock-pretreated control). In vivo epigenetic therapy enhanced the response of adenocarcinoma PDX to irinotecan.

Taken together, these data do not support broadly applicable epigenetic priming in NSCLC. Priming effects may be context-specific, dependent on both tumor and host factors. Further preclinical study is necessary to determine whether, and in which contexts, priming with epigenetic therapy has potential to enhance chemotherapeutic efficacy in NSCLC patients.


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