期刊
NATURE REVIEWS DRUG DISCOVERY
卷 20, 期 10, 页码 741-769出版社
NATURE PORTFOLIO
DOI: 10.1038/s41573-021-00209-1
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资金
- Cancer Research UK [C23338/A25722]
- UK Biotechnology and Biological Sciences Research Council [BB/I007806/1, BB/M013278/1, BB/R017972/1]
- UK NIHR University College London Hospitals Biomedical Research Centre
- NCI [R01 CA 213442]
- Gilead Sciences
- Verastem and TG Therapeutics
- Wellcome Trust [095691/Z/11/Z]
- Medical Research Council [MR/M012328/2]
- PTEN Research
- Wellcome Trust [095691/Z/11/Z] Funding Source: Wellcome Trust
Overactive PI3K is a frequently activated pathway in cancer, but therapeutic PI3K pathway inhibitors face challenges such as poor drug tolerance and resistance. Several targeted PI3K inhibitors have received regulatory approval, and their potential in cancer immunotherapy has been highlighted.
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 PI3K alpha isoform-selective inhibitor alpelisib for the treatment of breast cancer and inhibitors mainly aimed at the leukocyte-enriched PI3K delta 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 PI3K alpha and PI3K delta 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 PI3K alpha and PI3K delta - the key targets of currently approved PI3K inhibitors, highlighting lessons learned and future opportunities.
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