title: 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.
authors.affiliation: Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108, USA. sbelinsk@LRRI.org
authors.forename: Steven A
authors.initials: SA
authors.lastname: Belinsky
authors.forename: Marcie J
authors.initials: MJ
authors.lastname: Grimes
authors.forename: Maria A
authors.initials: MA
authors.lastname: Picchi
authors.forename: Hugh D
authors.initials: HD
authors.lastname: Mitchell
authors.forename: Chris A
authors.initials: CA
authors.lastname: Stidley
authors.forename: Yohannes
authors.initials: Y
authors.lastname: Tesfaigzi
authors.forename: Meghan M
authors.initials: MM
authors.lastname: Channell
authors.forename: Yanbin
authors.initials: Y
authors.lastname: Liu
authors.forename: Robert A
authors.initials: RA
authors.lastname: Casero
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Baylin
authors.forename: Mathew D
authors.initials: MD
authors.lastname: Reed
authors.forename: Carmen S
authors.initials: CS
authors.lastname: Tellez
authors.forename: Thomas H
authors.initials: TH
authors.lastname: March
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001374:Azacitidine / Q000008:administration & dosage; D001549:Benzamides / Q000008:administration & dosage; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects; D044127:Epigenesis, Genetic / Q000187:drug effects; D020869:Gene Expression Profiling; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D011725:Pyridines / Q000008:administration & dosage; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D001549:Benzamides; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D011725:Pyridines; C118739:entinostat; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D001374:Azacitidine