PI3K inhibitors are finally coming of age

• Published in: Nature reviews. Drug discovery Vol. 20; no. 10; pp. 741 - 769
• Main Authors: Vanhaesebroeck, Bart, Perry, Matthew W. D., Brown, Jennifer R., André, Fabrice, Okkenhaug, Klaus
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2021; Nature Publishing Group
• Subjects: 631/154; 631/154/309/555; Animals; Antimitotic agents; Antineoplastic agents; Biomedical and Life Sciences; Biomedicine; Biotechnology; Breast cancer; Cancer; Cancer cells; Cancer Research; Cellular signal transduction; Control; Drug resistance; Forecasts and trends; Growth; Health aspects; Humans; Immune System Diseases - drug therapy; Immune System Diseases - genetics; Immunotherapy; Inhibitor drugs; Medicinal Chemistry; Molecular Medicine; Neoplasms - drug therapy; Neoplasms - genetics; Pharmacology/Toxicology; Phosphatidylinositol 3-Kinases - drug effects; Phosphatidylinositol 3-Kinases - metabolism; Phosphoinositide-3 Kinase Inhibitors - pharmacology; Phosphoinositide-3 Kinase Inhibitors - therapeutic use; Phosphoinositides; Physiological aspects; Regulatory approval; Review Article; Europe
• ISSN: 1474-1776; 1474-1784; 1474-1784
• DOI: 10.1038/s41573-021-00209-1

Overactive phosphoinositide 3-kinase (PI3K) in cancer and immune dysregulation has spurred extensive efforts to develop therapeutic PI3K inhibitors. Although progress has been hampered by issues such as poor drug tolerance and drug resistance, several PI3K inhibitors have now received regulatory approval — the PI3Kα isoform-selective inhibitor alpelisib for the treatment of breast cancer and inhibitors mainly aimed at the leukocyte-enriched PI3Kδ in B cell malignancies. In addition to targeting cancer cell-intrinsic PI3K activity, emerging evidence highlights the potential of PI3K inhibitors in cancer immunotherapy. This Review summarizes key discoveries that aid the clinical translation of PI3Kα and PI3Kδ inhibitors, highlighting lessons learnt and future opportunities PI3K signalling is one of the most frequently aberrantly activated pathways in cancer. However, the development of therapeutic PI3K pathway inhibitors has faced challenges including poor drug tolerance and drug resistance. Here, Vanhaesebroeck et al. review efforts to understand and therapeutically exploit the biology of PI3Kα and PI3Kδ — the key targets of currently approved PI3K inhibitors, highlighting lessons learned and future opportunities.