Akt-targeted therapy as a promising strategy to overcome drug resistance in breast cancer – A comprehensive review from chemotherapy to immunotherapy. (June 2020)

• Record Type: Journal Article
• Authors: Jabbarzadeh Kaboli, Parham; Salimian, Fatemeh; Aghapour, Sevil; Xiang, Shixin; Zhao, Qijie; Li, Mingxing; Wu, Xu; Du, Fukuan; Zhao, Yueshui; Shen, Jing; Cho, Chi Hin; Xiao, Zhangang
• Is Part Of: Pharmacological research. Volume 156(2020)
• Publication Date: 2020-06
• Subjects: ABC ATP-binding cassette -- ADR Adriamycin -- AI Aromatase inhibitor -- ARE Anti-oxidant response element -- BAX BCL-2-associated X protein -- BBB Blood-brain barrier -- BCSC Breast cancer stem cell -- BRD4 Bromodomain-containing protein 4 -- BRCA1 Breast cancer tumor suppressor 1 -- CaM Calcium-dependent calmodulin -- CBP cAMP response element-binding protein (CREB)-binding protein -- CCN5 Cysteine rich 61/connective tissue growth factor -- CHP2 Calcineurin B homologous protein 2 -- CIP2A Cancerous inhibitor of PP2A -- c-Jun AP-1 transcription factor subunit -- CSC Cancer stem cell -- CSN COP9 signalosome complex -- DNMT DNA methyl transferase -- DUBs Deubiquitinating enzymes -- EGFR Epidermal growth factor receptor -- EMT Epithelial to mesenchymal transition -- ER Estrogen receptor -- ESR Estrogen receptor gene -- ETC Electron transport chain -- FIH-1 Factor-inhibiting HIF-1 -- FoxO1/3 Forkhead box O1/3 -- G-6-P Glucose-6-phosphate -- GNRHR Gonadotropin-releasing hormone (GnRH) receptor -- GRP75 Glucose-regulated protein 75 chaperone -- GSK-3 Glycogen synthase kinase 3 -- HAT Histone acetyl transferase -- Her2 Human epidermal growth factor receptor 2 -- HDAC Histone deacetylase -- HIF-1α Hypoxia-inducible factor-1α -- HK2 Hexokinase 2 -- HM Hydrophobic motif -- HO-1 Heme oxygenase-1 -- HRE Hypoxia-responsive element -- HSF1 Heat shock factor 1 -- HSP90 Heat shock protein 90 -- I2PP2A Oncogenic inhibitor of PP2A (SET) -- IGF-1 Insulin-like growth factor 1 -- IKK Inhibitor of NF-κB kinase -- IP3R Inositol trisphosphate receptor -- IRF1 Interferon regulatory factor 1 -- JAK Janus Kinase -- KD Kinase domain -- Keap1 Kelch-like ECH-associated protein 1 -- KLF5 Kruppel like factor 5 -- LC3 Microtubule-associated protein 1A/1B-light chain 3 -- LDHA Lactate dehydrogenase A subunit -- MAM Mitochondria-associated endoplasmic reticulum membranes -- MEK Mitogen-activated protein kinase kinase -- MRP1 Multidrug resistance protein 1 -- mTORC1 Mammalian target of rapamycin complex 1 -- mTORC2 Rapamycin-insensitive companion of mTOR complex -- NADD4 Neural precursor cell expressed developmentally down-regulated protein 4 -- NHE1 Na+/H+ exchanger -- NF-κB Nuclear factor kappa-light-chain -- NQO1 NAD(P)H quinone dehydrogenase 1 -- Nrf2 Nuclear factor erythroid 2-related factor 2 -- PAK1 p21 (RAC1) activated kinase 1 -- PD-L1 Protein programmed cell death-ligand -- PDH Pyruvate dehydrogenase -- PDK1 Pyruvate dehydrogenase kinase 1 -- PDPK1 3-Phosphoinositide dependent protein kinase 1 -- PHD Pleckstrin homology domain -- PI3K Phosphoinositide 3-kinase -- PKB Protein kinase B (Akt) -- PP2A Protein phosphatase 2 -- PPARg Peroxisome proliferator-activated receptor gamma (PPAR-γ) -- PTEN Phosphatase and tensin homolog -- Rictor Rapamycin-insensitive companion of mTOR -- RTK Receptor tyrosine kinase -- S6K S6 ribosomal protein kinase -- SALL2 Spalt-like transcription factor 2 -- SIRT1 NAD+-dependent deacetylase sirtuin-1 -- Skp2 S-phase kinase associated protein 2 -- SOD Superoxide dismutase -- STAT Signal transducer and activator of transcription -- SUMO Small Ubiquitin-like Modifier -- TCA Tricarboxylic acid cycle -- TIM Translocase of inner membrane -- TKI Tyrosine kinase inhibitor -- TKT Transketolase -- TOM Translocase of outer membrane -- TRAF Tumor necrosis factor (TNF) receptor associated factor -- TRPC1 Transient receptor potential cation channel subfamily C (canonical) member 1 -- TRPM2 Transient receptor potential cation channel subfamily M member 2 -- UEV1A Ubiquitin-conjugating enzyme E2 variant 1 -- USP18 Ubiquitin specific peptidase 18 -- VDAC Voltage-dependent anion-selective channel -- VHL von Hippel–Lindau protein; Akt -- Protein kinase B -- Breast cancer -- Drug resistance -- Targeted therapy -- Hypoxic conditions; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2020.104806
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Highlights: Akt as the master regulator of drug resistance in breast cancer is addressed in this review. Metabolic reprogramming induced by Akt regulates oncogenic signaling in hypoxic condition. Akt regulates anti-oxidant signaling and upregulates genes related to multi-drug resistance (MDR). Akt activates PD-L1 expression by having crosstalk with NF-κB and MAPK signaling pathways. Akt inhibitors are able to suppress maintenance of breast cancer stem cells and the metabolism of hypoxic condition. Abstract: Breast cancer is the most frequently occurring cancer in women. Chemotherapy in combination with immunotherapy has been used to treat breast cancer. Atezolizumab targeting the protein programmed cell death-ligand (PD-L1) in combination with paclitaxel was recently approved by the Food and Drug Administration (FDA) for Triple-Negative Breast Cancer (TNBC), the most incurable type of breast cancer. However, the use of such drugs is restricted by genotype and is effective only for those TNBC patients expressing PD-L1. In addition, resistance to chemotherapy with drugs such as lapatinib, geftinib, and tamoxifen can develop. In this review, we address chemoresistance in breast cancer and discuss Akt as the master regulator of drug resistance and several oncogenic mechanisms in breast cancer. Akt not only directly interacts with the mitogen-activated protein (MAP) kinase signaling pathway to affect PD-L1 expression, but also has crosstalk with Notch and Wnt/β-catenin signaling pathways involved in cell migration and breast cancer stem cell integrity. In this review, we discuss the effects of tyrosine kinase inhibitors on Akt activation as well as the mechanism of Akt signaling in drug resistance. Akt also has a crucial role in mitochondrial metabolism and migrates into mitochondria to remodel breast cancer cell metabolism while also functioning in responses to hypoxic conditions. The Akt inhibitors ipatasertib, capivasertib, uprosertib, and MK-2206 not only suppress cancer cell proliferation and metastasis, but may also inhibit cytokine regulation and PD-L1 expression. Ipatasertib and uprosertib are undergoing clinical investigation to treat TNBC. Inhibition of Akt and its regulators can be used to control breast cancer progression and also immunosuppression, while discovery of additional compounds that target Akt and its modulators could provide solutions to resistance to chemotherapy and immunotherapy.