Sensitization of retinoids and corticoids to epigenetic drugs in MYC-activated lung cancers by antitumor reprogramming

• Published in: Oncogene Vol. 36; no. 9; pp. 1287 - 1296
• Main Authors: Romero, O A, Verdura, S, Torres-Diz, M, Gomez, A, Moran, S, Condom, E, Esteller, M, Villanueva, A, Sanchez-Cespedes, M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02-03-2017; Nature Publishing Group
• Subjects: 38/39; 38/90; 45/61; 64/60; 692/53/2423; 82/51; Animals; Antimetabolites, Antineoplastic - pharmacology; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Azacitidine - pharmacology; Azacytidine; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; BRG1 protein; Cell Biology; Cell proliferation; Cell Proliferation - drug effects; Cell viability; Chromatin; Chromatin remodeling; Corticosteroid drugs; Corticosteroids; DNA Helicases - genetics; DNA Methylation; Dosage and administration; Drug Resistance, Neoplasm - drug effects; Drug therapy; Epigenetic inheritance; Epigenetics; Gene expression; Glucocorticoids; Glucocorticoids - pharmacology; Health aspects; Histone Deacetylase Inhibitors - pharmacology; Human Genetics; Humans; Hydroxamic Acids - pharmacology; Internal Medicine; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Male; Medicine; Medicine & Public Health; Mice; Mice, Nude; Mutation - genetics; Myc protein; Nuclear Proteins - genetics; Oncology; original-article; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Retinoids; Transcription Factors - genetics; Tretinoin - pharmacology; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2016.296

Components of the SWI/SNF chromatin remodeling complex, including BRG1 (also SMARCA4), are inactivated in cancer. Among other functions, SWI/SNF orchestrates the response to retinoid acid (RA) and glucocorticoids (GC) involving downregulation of MYC. The epigenetic drugs SAHA and azacytidine, as well as RA and GC, are currently being used to treat some malignancies but their therapeutic potential in lung cancer is not well established. Here we aimed to determine the possible therapeutic effects of azacytidine and SAHA (A/S) alone or in combination with GC plus RA (GC/RA) in lung cancers with either
BRG1
inactivation or
MYC
amplification.
In vitro
, responses to GC/RA treatment were more effective in
MYC
-amplified cells. These effects were mediated by BRG1 and involved a reprogramming towards prodifferentiation gene expression signatures and downregulation of MYC. In
MYC
-amplified cells, administration of GC/RA enhanced the cell growth inhibitory effects of A/S which, in turn, accentuated the prodifferentiation features promoted by GC/RA. Finally, these treatments improved overall survival of mice orthotopically implanted with
MYC
-amplified, but not
BRG1
-mutant, cells and reduced tumor cell viability and proliferation. We propose that the combination of epigenetic treatments with retinoids and corticoids of MYC-driven lung tumors constitute a strategy for therapeutic intervention in this otherwise incurable disease.