title: Addressing the elephant in the room, therapeutic resistance in non-small cell lung cancer, with epigenetic therapies.
abstract: Like Chinese boxes nesting inside each other, the classification of non-small cell lung cancer (NSCLC) is subdivided into smaller and smaller subtypes on the basis of histological and molecular attributes. The latter characterizes NSCLC by its molecular alterations and the identification of inhibitors that target these cancer-specific "driver" mutations. Despite the initial promise of precision-guided therapies to inhibit a finer and finer array of molecular subcategories, despite even the curative potential of immunotherapeutic checkpoint blockade, in particular, casualties still abound and true clinical success stories are few and far between; the ever-present, if sometimes unmentioned, "elephant in the room", is the acquisition of resistance, which, sooner or later, rears its ugly head to undermine treatment success and shorten survival. Emerging data suggests that epigenetic therapies are able to reprogram the aberrant tumor-associated epigenome and 'tame the beast of resistance', thereby prolonging survival. This article reviews the role of epigenetic dysregulation in NSCLC, explores PFS2 as a possible surrogate endpoint, briefly mentions possible biomarkers and highlights combinatorial treatment epigenetic strategies to "prime" tumors and reverse resistance.
authors.affiliation: Walter Reed National Military Medical Center, Bethesda, MD, USA.
authors.forename: Corey A
authors.initials: CA
authors.lastname: Carter
authors.affiliation: National Naval Medical Center, Bethesda, MD, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Zeman
authors.affiliation: Uniformed Services University of The Health Sciences, Bethesda, MD, USA.
authors.forename: Regina M
authors.initials: RM
authors.lastname: Day
authors.affiliation: Uniformed Services University of The Health Sciences, Bethesda, MD, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Richard
authors.affiliation: InterWest Partners, Menlo Park, CA, USA.
authors.forename: Arnold
authors.initials: A
authors.lastname: Oronsky
authors.affiliation: CFLS Data, Mountain View, CA, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Oronsky
authors.affiliation: EpicentRx, Inc, Mountain View, CA, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Lybeck
authors.affiliation: EpicentRx, Inc, Mountain View, CA, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Scicinski
authors.affiliation: EpicentRx, Inc, Mountain View, CA, USA.
authors.forename: Bryan
authors.initials: B
authors.lastname: Oronsky
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001374:Azacitidine / Q000494:pharmacology; D001384:Azetidines / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D018899:CpG Islands; D019175:DNA Methylation; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D044127:Epigenesis, Genetic; D006657:Histones / Q000737:chemistry; D006801:Humans; D006830:Hydralazine / Q000494:pharmacology; D007167:Immunotherapy / Q000379:methods; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D058990:Molecular Targeted Therapy; D009154:Mutation; D009364:Neoplasm Recurrence, Local; D009574:Nitro Compounds / Q000494:pharmacology; D000077594:Nivolumab; D011379:Prognosis; D011725:Pyridines / Q000494:pharmacology; D016896:Treatment Outcome; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D001384:Azetidines; D001549:Benzamides; D014408:Biomarkers, Tumor; D006657:Histones; D009574:Nitro Compounds; D011725:Pyridines; C577469:RRx-001; C118739:entinostat; D006830:Hydralazine; D000077594:Nivolumab; D014635:Valproic Acid; D001374:Azacitidine
keywords: epigenetics; non small cell lung cancer; oncology; resistance