title: Resistance to everolimus driven by epigenetic regulation of MYC in ER+ breast cancers.
abstract: Acquired resistance to PI3K/mTOR/Akt pathway inhibitors is often associated with compensatory feedback loops involving the activation of oncogenes. Here, we have generated everolimus resistance in ER+ breast cancer cells and in long-term estrogen deprived (LTED) models that mimic progression on anti-estrogens. This allowed us to uncover MYC as a driver of mTOR inhibitor resistance. We demonstrate that both everolimus resistance and acute treatment of everolimus can lead to the upregulation of MYC mRNA, protein expression and, consequently, the enrichment of MYC signatures as revealed by RNA sequencing data. Depletion of MYC resulted in resensitization to everolimus, confirming its functional importance in this setting. Furthermore, ChIP assays demonstrate that MYC upregulation in the everolimus resistant lines is mediated by increased association of the BRD4 transcription factor with the MYC gene. Finally, JQ1, a BRD4 inhibitor combined with everolimus exhibited increased tumor growth inhibition in 3D Matrigel models and an in vivo xenograft model. These data suggest that MYC plays an important role in mediating resistance to everolimus in ER+ and ER+/LTED models. Furthermore, given the regulation ofMYCby BRD4 in this setting, these data have implications for increased therapeutic potential of combining epigenetic agents with mTOR inhibitors to effectively downregulate otherwise difficult to target transcription factors such as MYC.
authors.affiliation: AstraZeneca, R&D Boston, Waltham, MA.
authors.forename: Teeru
authors.initials: T
authors.lastname: Bihani
authors.affiliation: AstraZeneca, R&D Boston, Waltham, MA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Ezell
authors.affiliation: AstraZeneca, R&D Boston, Waltham, MA.
authors.forename: Brendon
authors.initials: B
authors.lastname: Ladd
authors.affiliation: AstraZeneca, R&D Boston, Waltham, MA.
authors.forename: Shaun E
authors.initials: SE
authors.lastname: Grosskurth
authors.affiliation: AstraZeneca, R&D Boston, Waltham, MA.
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Mazzola
authors.affiliation: AstraZeneca, R&D Boston, Waltham, MA.
authors.forename: Mark
authors.initials: M
authors.lastname: Pietras
authors.affiliation: AstraZeneca, R&D Boston, Waltham, MA.
authors.forename: Corinne
authors.initials: C
authors.lastname: Reimer
authors.affiliation: AstraZeneca, R&D Boston, Waltham, MA.
authors.forename: Michael
authors.initials: M
authors.lastname: Zinda
authors.affiliation: AstraZeneca, R&D Boston, Waltham, MA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Fawell
authors.affiliation: AstraZeneca, R&D Boston, Waltham, MA.
authors.forename: Celina M
authors.initials: CM
authors.lastname: D'Cruz
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001381:Azepines / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004357:Drug Synergism; D044127:Epigenesis, Genetic / Q000187:drug effects*; D000068338:Everolimus / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015151:Immunoblotting; D061986:MCF-7 Cells; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D011960:Receptors, Estrogen / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000092468:Bromodomain Containing Proteins
chemical_list: D000970:Antineoplastic Agents; D001381:Azepines; D018797:Cell Cycle Proteins; D000068338:Everolimus; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D011960:Receptors, Estrogen; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins