Combination Therapy with Vidaza and Entinostat Suppresses Tumor Growth and Reprograms the Epigenome in an Orthotopic Lung Cancer Model

Abstract

Epigenetic therapy for solid tumors could benefit from an in vivo model that defines tumor characteristics of responsiveness and resistance to facilitate patient selection. Here we report that combining the histone deacetylase inhibitor entinostat with the demethylating agent vidaza profoundly affected growth of K-ras/ p53 mutant lung adenocarcinomas engrafted orthotopically in immunocompromised nude rats by targeting and ablating pleomorphic cells that occupied up to 75% of the tumor masses. A similar reduction in tumor burden was seen with epigenetic therapy in K-ras or EGFR mutant tumors growing orthotopically. Increased expression of proapoptotic genes and the cyclin-dependent kinase inhibitor p21 was seen. Hundreds of genes were demethylated highlighted by the reexpression of polycomb-regulated genes coding for transcription factor binding proteins and the p16 gene, a key regulator of the cell cycle. Highly significant gene expression changes were seen in key regulatory pathways involved in cell cycle, DNA damage, apoptosis, and tissue remodeling. These findings show the promise for epigenetic therapy in cancer management and provide an orthotopic lung cancer model that can assess therapeutic efficacy and reprogramming of the epigenome in tumors harboring different genetic and epigenetic profiles to guide use of these drugs. Cancer Res; 71(2); 454-62. Ó2011 AACR.

Deletion of the de novo DNA methyltransferase Dnmt3a promotes lung tumor progression

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Epigenetic modifications and p21-cyclin B1 nexus in anticancer effect of histone deacetylase inhibitors in combination with silibinin on non-small cell lung cancer cells

“…2 The high incidence and associated mortality of lung cancer have triggered a renewed focus on the study of targeted therapies against epigenetic events that become altered during the pathogenesis of this malignancy. [2][3][4][5] Epigenetic events are heritable, yet reversible, dynamic changes in the genome that can occur in response to the environment, diet, disease and aging; they manifest in the form of DNA methylation, modifications of histone tails and non-coding RNAs. [5][6][7][8] Among these epigenetic events, the silencing of tumor suppressor…”

Epigenetic therapy approaches in non-small cell lung cancer: Update and perspectives

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