title: AKT Antagonist AZD5363 Influences Estrogen Receptor Function in Endocrine-Resistant Breast Cancer and Synergizes with Fulvestrant (ICI182780) In Vivo.
abstract: PI3K/AKT/mTOR signaling plays an important role in breast cancer. Its interaction with estrogen receptor (ER) signaling becomes more complex and interdependent with acquired endocrine resistance. Targeting mTOR combined with endocrine therapy has shown clinical utility; however, a negative feedback loop exists downstream of PI3K/AKT/mTOR. Direct blockade of AKT together with endocrine therapy may improve breast cancer treatment. AZD5363, a novel pan-AKT kinase catalytic inhibitor, was examined in a panel of ER(+) breast cancer cell lines (MCF7, HCC1428, T47D, ZR75.1) adapted to long-term estrogen deprivation (LTED) or tamoxifen (TamR). AZD5363 caused a dose-dependent decrease in proliferation in all cell lines tested (GI50 < 500 nmol/L) except HCC1428 and HCC1428-LTED. T47D-LTED and ZR75-LTED were the most sensitive of the lines (GI50 ∼ 100 nmol/L). AZD5363 resensitized TamR cells to tamoxifen and acted synergistically with fulvestrant. AZD5363 decreased p-AKT/mTOR targets leading to a reduction in ERα-mediated transcription in a context-specific manner and concomitant decrease in recruitment of ER and CREB-binding protein (CBP) to estrogen response elements located on the TFF1, PGR, and GREB1 promoters. Furthermore, AZD5363 reduced expression of cell-cycle-regulatory proteins. Global gene expression highlighted ERBB2-ERBB3, ERK5, and IGFI signaling pathways driven by MYC as potential feedback-loops. Combined treatment with AZD5363 and fulvestrant showed synergy in an ER(+) patient-derived xenograft and delayed tumor progression after cessation of therapy. These data support the combination of AZD5363 with fulvestrant as a potential therapy for breast cancer that is sensitive or resistant to E-deprivation or tamoxifen and that activated AKT is a determinant of response, supporting the need for clinical evaluation.
authors.affiliation: Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, United Kingdom.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Ribas
authors.affiliation: Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, United Kingdom.
authors.forename: Sunil
authors.initials: S
authors.lastname: Pancholi
authors.affiliation: Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, United Kingdom.
authors.forename: Stephanie K
authors.initials: SK
authors.lastname: Guest
authors.affiliation: Department of Translational Research, Institut Curie, Paris, France.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Marangoni
authors.affiliation: Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, United Kingdom.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Gao
authors.affiliation: Department of Translational Research, Institut Curie, Paris, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Thuleau
authors.affiliation: Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, United Kingdom.
authors.forename: Nikiana
authors.initials: N
authors.lastname: Simigdala
authors.affiliation: Oncology Innovative Medicines, AstraZeneca, United Kingdom.
authors.forename: Urszula M
authors.initials: UM
authors.lastname: Polanska
authors.affiliation: Oncology Innovative Medicines, AstraZeneca, United Kingdom.
authors.forename: Hayley
authors.initials: H
authors.lastname: Campbell
authors.affiliation: Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, United Kingdom.
authors.forename: Aradhana
authors.initials: A
authors.lastname: Rani
authors.affiliation: Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, United Kingdom.
authors.forename: Gianmaria
authors.initials: G
authors.lastname: Liccardi
authors.affiliation: Royal Marsden Hospital, London, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: Johnston
authors.affiliation: Oncology Innovative Medicines, AstraZeneca, United Kingdom.
authors.forename: Barry R
authors.initials: BR
authors.lastname: Davies
authors.affiliation: Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, United Kingdom. Royal Marsden Hospital, London, United Kingdom.
authors.forename: Mitch
authors.initials: M
authors.lastname: Dowsett
authors.affiliation: Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, United Kingdom. lesley-ann.martin@icr.ac.uk.
authors.forename: Lesley-Ann
authors.initials: LA
authors.lastname: Martin
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016000:Cluster Analysis; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D015533:Transcriptional Activation; D023041:Xenograft Model Antitumor Assays
chemical_list: D018931:Antineoplastic Agents, Hormonal; D004958:Estradiol; D000077267:Fulvestrant; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D016271:Proto-Oncogene Proteins c-myc; D011743:Pyrimidines; D011758:Pyrroles; D011960:Receptors, Estrogen; D058570:TOR Serine-Threonine Kinases; C575618:capivasertib