title: PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast cancer.
abstract: Activating mutations of PIK3CA are the most frequent genomic alterations in estrogen receptor (ER)-positive breast tumors, and selective phosphatidylinositol 3-kinase α (PI3Kα) inhibitors are in clinical development. The activity of these agents, however, is not homogeneous, and only a fraction of patients bearing PIK3CA-mutant ER-positive tumors benefit from single-agent administration. Searching for mechanisms of resistance, we observed that suppression of PI3K signaling results in induction of ER-dependent transcriptional activity, as demonstrated by changes in expression of genes containing ER-binding sites and increased occupancy by the ER of promoter regions of up-regulated genes. Furthermore, expression of ESR1 mRNA and ER protein were also increased upon PI3K inhibition. These changes in gene expression were confirmed in vivo in xenografts and patient-derived models and in tumors from patients undergoing treatment with the PI3Kα inhibitor BYL719. The observed effects on transcription were enhanced by the addition of estradiol and suppressed by the anti-ER therapies fulvestrant and tamoxifen. Fulvestrant markedly sensitized ER-positive tumors to PI3Kα inhibition, resulting in major tumor regressions in vivo. We propose that increased ER transcriptional activity may be a reactive mechanism that limits the activity of PI3K inhibitors and that combined PI3K and ER inhibition is a rational approach to target these tumors.
authors: Human Oncology and Pathogenesis Program and Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA.
authors: Ana
authors: A
authors: Bosch
authors: Human Oncology and Pathogenesis Program and Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA.
authors: Zhiqiang
authors: Z
authors: Li
authors: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, 524 Burrill Hall, Urbana, IL 61801, USA.
authors: Anna
authors: A
authors: Bergamaschi
authors: Human Oncology and Pathogenesis Program and Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA.
authors: Haley
authors: H
authors: Ellis
authors: Human Oncology and Pathogenesis Program and Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA.
authors: Eneda
authors: E
authors: Toska
authors: Translational Genomics Group, Vall d'Hebron Institute of Oncology (VHIO), Passeig Vall d'Hebron 119-129, Barcelona 08035, Spain. Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute, Hospital Clinic Barcelona, C/Rosselló 149-153, Barcelona 08035, Spain.
authors: Aleix
authors: A
authors: Prat
authors: Massachusetts General Hospital Cancer Center and Harvard Medical School, 425 13th Street, Charlestown, MA 02129, USA.
authors: Jessica J
authors: JJ
authors: Tao
authors: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors: Daniel E
authors: DE
authors: Spratt
authors: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors: Nerissa T
authors: NT
authors: Viola-Villegas
authors: Human Oncology and Pathogenesis Program and Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA.
authors: Pau
authors: P
authors: Castel
authors: Molecular Pharmacology and Chemistry Program and Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors: Gerard
authors: G
authors: Minuesa
authors: Human Oncology and Pathogenesis Program and Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA.
authors: Natasha
authors: N
authors: Morse
authors: Department of Medical Oncology, VHIO, Barcelona 08035, Spain. Universitat Autònoma de Barcelona, Plaza Cívica, Campus UAB, 08193 Bellaterra, Spain.
authors: Jordi
authors: J
authors: Rodón
authors: Experimental Therapeutics Group, VHIO, Barcelona 08035, Spain.
authors: Yasir
authors: Y
authors: Ibrahim
authors: Department of Medical Oncology, VHIO, Barcelona 08035, Spain.
authors: Javier
authors: J
authors: Cortes
authors: Department of Medical Oncology, VHIO, Barcelona 08035, Spain.
authors: Jose
authors: J
authors: Perez-Garcia
authors: Translational Genomics Group, Vall d'Hebron Institute of Oncology (VHIO), Passeig Vall d'Hebron 119-129, Barcelona 08035, Spain.
authors: Patricia
authors: P
authors: Galvan
authors: Experimental Therapeutics Group, VHIO, Barcelona 08035, Spain.
authors: Judit
authors: J
authors: Grueso
authors: Experimental Therapeutics Group, VHIO, Barcelona 08035, Spain.
authors: Marta
authors: M
authors: Guzman
authors: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors: John A
authors: JA
authors: Katzenellenbogen
authors: Molecular Pharmacology and Chemistry Program and Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors: Michael
authors: M
authors: Kharas
authors: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Molecular Pharmacology and Chemistry Program and Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors: Jason S
authors: JS
authors: Lewis
authors: Breast Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors: Maura
authors: M
authors: Dickler
authors: Experimental Therapeutics Group, VHIO, Barcelona 08035, Spain.
authors: Violeta
authors: V
authors: Serra
authors: Molecular Pharmacology and Chemistry Program and Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors: Neal
authors: N
authors: Rosen
authors: Human Oncology and Pathogenesis Program and Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA. Breast Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY 10065, USA. chandars@mskcc.org scaltrim@mskcc.org baselgaj@mskcc.org.
authors: Sarat
authors: S
authors: Chandarlapaty
authors: Human Oncology and Pathogenesis Program and Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA. chandars@mskcc.org scaltrim@mskcc.org baselgaj@mskcc.org.
authors: Maurizio
authors: M
authors: Scaltriti
authors: Human Oncology and Pathogenesis Program and Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA. Breast Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY 10065, USA. chandars@mskcc.org scaltrim@mskcc.org baselgaj@mskcc.org.
authors: José
authors: J
authors: Baselga
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004721:Endoplasmic Reticulum / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012107:Research Design; D015398:Signal Transduction; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D047628:Estrogen Receptor alpha; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013844:Thiazoles; C506487:ESR1 protein, human; C585539:Alpelisib