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

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

doi:10.18632/oncotarget.2695

Frank P Vendetti, John Wrangle + Show 7 more

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https://doi.org/10.18632/oncotarget.2695

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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 patient derived 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.

Highlights

Non-small cell lung cancers (NSCLC) account for approximately 80% of all cases of lung cancer, a disease which remains the leading cause of cancer-related mortality worldwide [1]
We recently explored the potential efficacy of a combinatorial epigenetic therapy strategy for the treatment of recurrent metastatic NSCLC, using the demethylating agent, azacitidine (Aza), and the class I specific histone deacetylase inhibitor (HDI), entinostat [11]
We sought to determine whether epigenetic therapy sensitizes NSCLC cell lines to subsequent chemotherapy in vitro

Summary

Introduction

Non-small cell lung cancers (NSCLC) account for approximately 80% of all cases of lung cancer, a disease which remains the leading cause of cancer-related mortality worldwide [1]. NSCLC is still frequently treated with conventional cytotoxic chemotherapy, typically a platinum agent in combination with a taxane or gemcitabine in first line therapy This approach is hampered by limited efficacy, high toxicity, resistance, and recurrence of disease, which highlights the need for more effective treatments. A similar scenario was previously observed in a pilot phase I/II study of the demethylating agent decitabine in stage IV NSCLC patients, with one patient receiving chemotherapy aprroximately six months after decitabine, and surviving 81 months [12] These observations, representing a small sample size, suggest the potential for epigenetic therapy to sensitize NSCLC to subsequent chemotherapy. Additional supporting evidence for a chemotherapy priming effect comes from recent clinical trials in other solid tumors: two recent reports provide evidence that treatment with a demethylating agent (azacitidine or decitabine) can re-sensitize resistant and refractory ovarian tumors to platinum chemotherapy [13, 14]

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