title: AKT signaling in ERBB2-amplified breast cancer.
abstract: The PI3K/AKT pathway is the focus of several targeted therapeutic agents for a variety of malignancies. In ERBB2-amplified breast cancer, the hyperactivation of this signaling cascade is associated with resistance to ERBB2-targeted therapy. This can occur through gain-of-function alterations or compensatory mechanisms that enter into play upon pharmacological pressure. The strong rationale in combining anti-ERBB2 agents with PI3K/AKT inhibitors, together with the identification of genomic alterations conferring sensitivity to targeted inhibition, are guiding the design of clinical studies aimed at preventing the emergence of drug resistance and achieving more durable response. In the present review, we describe the involvement of this pathway in breast cancer pathogenesis, with an emphasis on AKT kinases, and provide insight into currently available targeted agents for the treatment of ERBB2-amplified breast cancer. Finally, we provide preliminary data on a novel AKT3 mutation detected in the context of resistance to anti-ERBB2 therapy as an example of genomics-based approaches towards uncovering novel actionable targets in this setting.
authors.affiliation: Memorial Sloan Kettering Cancer Center (MSKCC), Human Oncology and Pathogenesis Program (HOPP), NY, USA.
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Carmona
authors.affiliation: Unit of Investigative Clinical Oncology, Institute for Cancer Research and Treatment, Candiolo, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Montemurro
authors.affiliation: Bioinformatics Institute (A*STAR), #07-01 Matrix, 30 Biopolis Street #07-01, 138671, Singapore.
authors.forename: Srinivasaraghavan
authors.initials: S
authors.lastname: Kannan
authors.affiliation: Medical Oncology, Ospedale Civile di Saluzzo, Saluzzo, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Rossi
authors.affiliation: Bioinformatics Institute (A*STAR), #07-01 Matrix, 30 Biopolis Street #07-01, 138671, Singapore; Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, 117543, Singapore; School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, 637551, Singapore.
authors.forename: Chandra
authors.initials: C
authors.lastname: Verma
authors.affiliation: Memorial Sloan Kettering Cancer Center (MSKCC), Human Oncology and Pathogenesis Program (HOPP), NY, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA.
authors.forename: José
authors.initials: J
authors.lastname: Baselga
authors.affiliation: Memorial Sloan Kettering Cancer Center (MSKCC), Human Oncology and Pathogenesis Program (HOPP), NY, USA. Electronic address: scaltrim@mskcc.org.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Scaltriti
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D018734:Genes, erbB-2 / Q000235:genetics*; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: AKT3; Drug resistance; PI3K; Targeted therapy; Trastuzumab; mTOR