title: Evaluation of azacitidine and entinostat as sensitization agents to cytotoxic chemotherapy in preclinical models of non-small cell lung cancer.
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.
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD.
authors.forename: Frank P
authors.initials: FP
authors.lastname: Vendetti
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD.
authors.forename: Michael
authors.initials: M
authors.lastname: Topper
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD.
authors.forename: Peng
authors.initials: P
authors.lastname: Huang
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD.
authors.forename: Irina
authors.initials: I
authors.lastname: Dobromilskaya
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD.
authors.forename: Hariharan
authors.initials: H
authors.lastname: Easwaran
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD.
authors.forename: John
authors.initials: J
authors.lastname: Wrangle
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Baylin
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: J T
authors.initials: JT
authors.lastname: Poirier
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rudin
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D001374:Azacitidine / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival; D019175:DNA Methylation; D004353:Drug Evaluation, Preclinical; D044127:Epigenesis, Genetic; D005260:Female; D006657:Histones / Q000737:chemistry; D006801:Humans; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011725:Pyridines / Q000494:pharmacology*
chemical_list: D001549:Benzamides; D006657:Histones; D011725:Pyridines; C118739:entinostat; D000077146:Irinotecan; D001374:Azacitidine; D002166:Camptothecin