PI3K inhibition in breast cancer: Identifying and overcoming different flavors of resistance. (June 2021)

• Record Type: Journal Article
• Authors: Vitale, Silvia Rita; Martorana, Federica; Stella, Stefania; Motta, Gianmarco; Inzerilli, Nicola; Massimino, Michele; Tirrò, Elena; Manzella, Livia; Vigneri, Paolo
• Is Part Of: Critical reviews in oncology/hematology. Volume 162(2021)
• Publication Date: 2021-06
• Subjects: BYL719 alpelisib -- CDK 4/6 ciclin dependent kinase 4/6 -- FoxO Forkhead box protein O -- GDC-0032 taselisib -- GDC-0941 pictilisib -- IL-8 interleukin-8 -- NEK9 serine/threonine-protein kinase Nek9 -- p27Kip1 p27 kinase inhibitory protein 1 -- PDK1 3-phosphoinositide dependent kinase-1 -- RHEB RAS homolog enriched in brain -- S6K1 ribosomal protein S6 kinase -- 4E-BP1 eIF4E binding protein 1 -- AP-1 transcription factor subunit -- AP-1 activator protein-1 -- BAD BCL2 associated agonist of cell death -- BAX BCL2 associated X;BAY80-6946: copanlisib -- BCL2 B-cell lymphoma 2 -- BET Bromo- and Extra-Terminal proteins -- BKM-120 buparlisb -- c-JUN Jun proto-oncogene, COSMIC: Catalogue of Somatic Mutations in Cancer -- EGFR epidermal growth factor receptor -- eIF4E eukaryotic translation initiation factor 4E -- EMT epithelial to mesenchymal transition -- ERKs extracellular signal-regulated kinases -- ESCC esophageal squamous cell carcinomas -- FGFR fibroblast growth factor receptors -- FOS complex consisting of FBJ murine osteosarcoma viral oncogene -- FOSL1 FOS ligand 1 -- FOXO3 Forkhead box O3 -- GPCR G-protein coupled receptor -- GSK3b b-catenin signaling -- GSK3α/ β glycogen synthase kinase-3 α/ β -- GTPases related guanosine triphosphatases -- HER2- human epidermal growth factor receptor 2 negative -- HER3 human epidermal growth factor receptor 3 -- HNSCC head and neck squamous cell carcinomas -- HR+ hormone receptor positive -- IGF-1R insulin growth factor-1 receptor -- IL-6 interleukin-6 -- INPP4B inositol polyphosphate-4-phosphatase type II B -- IRS-1/2 insulin receptor substrate 1/2 -- IRS-2 insulin receptor substrate 2 -- JAKs Janus family of kinases -- MAPK mitogen-activated protein kinase -- MDM2 mouse double minute 2 homolog -- MEK mitogen-activated protein kinase kinase (MEK) -- mTOR mammalian target of rapamycin -- P21 Proto-Oncogene protein P21 -- PDX patient-derived xenograft -- PI3K phosphatidylinositol 3-kinase -- Pim1 proto-oncogene, serine/threonine kinase (PIM1) -- PIP2 phosphatidylinositol (4, 5)-bisphosphate -- PIP3 phosphatidylinositol (3, 4, 5)-trisphosphate -- PKB/AKT protein kinase B -- PLCg/PKC phospholipase Cg-protein kinase C -- JNK c-Jun N-terminal kinases -- PTEN phosphatase and tensin homolog -- RAS small rat sarcoma -- RSK3 ribosomal S6 kinases RPS6KA2 -- RSK4 ribosomal S6 kinases RPS6KA6 -- RTK receptor-coupled tyrosine kinases -- SGK1 serum/glucocorticoid regulated kinase 1 -- SH2 SRC Homology 2 domain -- SHIP1 SH2 domain-containing inositol polyphosphate 5-phosphatase 1 -- SKP2 S-phase kinase-associated protein 2 -- STATs signal transducers and activators of transcription -- TCF7 Transcription Factor 7 -- TNBC triple negative breast cancer -- TORC1 mTOR/Raptor complex -- TORC2 mTOR/Rictor complex -- TSC1/2 tuberous sclerosis complex 1 and 2;TSC2: TSC complex subunit 2 -- WGS whole genome sequencing -- WNT Wingless-type MMTV integration site family; PI3K -- PI3K/AKT/mToR pathway -- PI3K-inhibitors -- PIK3CA mutations -- Breast cancer; Oncology -- Periodicals; Hematology -- Periodicals; 616.994
• DOI: 10.1016/j.critrevonc.2021.103334
• Languages: English
• ISSNs: 1040-8428

Abstract

Graphical abstract: Highlights: Aberrant PI3K activation determines deregulation of the PI3K/AKT/mToR pathway. PIK3CA mutations exert both a prognostic and predictive role in breast cancer. Several biological mechanisms confer resistance to PI3K inhibition in breast cancer. Combination regimens might effectively overcome resistance to PI3K inhibition. Abstract: The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway is commonly deregulated in many human tumors, including breast cancer. Somatic mutations of the PI3K alpha catalytic subunit ( PIK3CA ) are the most common cause of pathway hyperactivation. Hence, several PI3K inhibitors have been investigated with one of them, alpelisib, recently approved for the treatment of endocrine sensitive, PIK3CA mutated, metastatic breast cancer. Unfortunately, all patients receiving a PI3K inhibitor eventually develop resistance to these compounds. Mechanisms of resistance include oncogenic PI3K alterations, pathway reactivation through upstream or downstream effectors and enhancement of parallel pro-survival pathways. We review the prognostic and predictive role of PI3K alterations in breast cancer, focusing on resistance to PI3K inhibitors and on biomarkers with potential clinical relevance. We also discuss combination strategies that may overcome resistance to PI3K inhibitors, thus increasing the efficacy of these drugs in breast cancer.