PI3K抑制剂在癌症治疗中的作用和未来的发展方向
Role and Future Directions of PI3K Inhibitors in Cancer Treatment
DOI: 10.12677/HJMCe.2023.112013, PDF,   
作者: 郝思远, 周庆发*:中国药科大学理学院,江苏 南京
关键词: PI3K抑制剂抗癌小分子抑制剂PI3K Inhibitors Anticancer Drugs Small Molecule Inhibitors
摘要: 磷酸肌醇3激酶(PI3K)–蛋白激酶B(PKB/AKT)–哺乳动物雷帕霉素靶蛋白(mTOR)轴是一个关键的信号转导系统,连接致癌基因和多个受体类别,参与许多重要的细胞功能。异常的PI3K信号通路是癌症中最常见的突变途径之一。由于PI3K/AKT/mTOR通路的致癌激活经常与其他信号网络的突变同时发生,且此类抑制剂有一定的耐药性,因此应考虑联合治疗。在这篇综述中,我们强调了PI3K通路知识的最新研究进展,并讨论了未来探索的方向。
Abstract: The phosphoinositol 3 kinase (PI3K)-protein kinase B (PKB/AKT) mammalian rapamycin target protein (mTOR) axis is a key signal transduction system that connects oncogenes and multiple receptor categories, participating in many important cellular functions. The abnormal PI3K signaling pathway is one of the most common mutation pathways in cancer. Due to the fact that carcinogenic activation of the PI3K/AKT/mTOR pathway often occurs simultaneously with mutations in other signaling networks, and such inhibitors have certain resistance, combination therapy should be considered. In this review, we highlight the latest research progress on PI3K pathway knowledge and discuss future directions for exploration.
文章引用:郝思远, 周庆发. PI3K抑制剂在癌症治疗中的作用和未来的发展方向[J]. 药物化学, 2023, 11(2): 100-107. https://doi.org/10.12677/HJMCe.2023.112013

参考文献

[1] Valastyan, S. and Weinberg, R.A. (2011) Tumor Metastasis: Molecular Insights and Evolving Paradigms. Cell, 147, 275-292. [Google Scholar] [CrossRef] [PubMed]
[2] Damineni, S., Rao, V.R., Kumar, S., et al. (2014) Germline Mutations of TP53 Gene in Breast Cancer. Tumor Biology, 35, 9219-9227. [Google Scholar] [CrossRef] [PubMed]
[3] Siegel, R.L., Miller, K.D., Wagle, N.S., et al. (2023) Cancer Sta-tistics, 2023. CA: A Cancer Journal for Clinicians, 73, 17-48. [Google Scholar] [CrossRef] [PubMed]
[4] 刘宗超, 李哲轩, 张阳, 等. 2020全球癌症统计报告解读[J]. 肿瘤综合治疗电子杂志, 2021, 7(2): 1-13.
[5] Lawrence, M.S., Stojanov, P., Mermel, C.H., et al. (2014) Discovery and Saturation Analysis of Cancer Genes across 21 Tumour Types. Nature, 505, 495-501. [Google Scholar] [CrossRef] [PubMed]
[6] Sirico, M., D’Angelo, A., Gianni, C., et al. (2023) Current State and Future Challenges for PI3K Inhibitors in Cancer Therapy. Cancers, 15, 703. [Google Scholar] [CrossRef] [PubMed]
[7] Hennessy, B.T., Smith, D.L., Ram, P.T., et al. (2005) Exploiting the PI3K/AKT Pathway for Cancer Drug Discovery. Nature Reviews Drug Discovery, 4, 988-1004. [Google Scholar] [CrossRef] [PubMed]
[8] Vanhaesebroeck, B., Guillermet-Guibert, J., Graupera, M., et al. (2010) The Emerging Mechanisms of Isoform-Specific PI3K Signalling. Nature Reviews Molecular Cell Biology, 11, 329-341. [Google Scholar] [CrossRef] [PubMed]
[9] Thorpe, L.M., Yuzugullu, H. and Zhao, J.J. (2015) PI3K in Cancer: Diver-gent Roles of Isoforms, Modes of Activation and Therapeutic Targeting. Nature Reviews Cancer, 15, 7-24. [Google Scholar] [CrossRef] [PubMed]
[10] Engelman, J.A. (2009) Targeting PI3K Signalling in Cancer: Opportunities, Challenges and Limitations. Nature Reviews Cancer, 9, 550-562. [Google Scholar] [CrossRef] [PubMed]
[11] Hanker, A.B., Kaklamani, V. and Arteaga, C.L. (2019) Challenges for the Clinical Development of PI3K Inhibitors: Strategies to Improve Their Impact in Solid Tumors What Limits the Success of PI3K Inhibitors? Cancer Discovery, 9, 482-491. [Google Scholar] [CrossRef
[12] Okkenhaug, K., Graupera, M. and Vanhaesebroeck, B. (2016) Targeting PI3K in Cancer: Impact on Tumor Cells, Their Protective Stroma, Angiogenesis, and Immunotherapy PI3K Isoform Function in the Tumor Stroma. Cancer Discovery, 6, 1090-1105. [Google Scholar] [CrossRef
[13] O’Donnell, J.S., Massi, D., Teng, M.W., et al. (2018) PI3K-AKT-mTOR Inhibition in Cancer Immunotherapy, Redux. Seminars in Cancer Biology, 48, 91-103. [Google Scholar] [CrossRef] [PubMed]
[14] Jean, S. and Kiger, A.A. (2014) Classes of Phosphoinositide 3-Kinases at a Glance. Journal of Cell Science, 127, 923-928. [Google Scholar] [CrossRef] [PubMed]
[15] Toker, A. and Cantley, L.C. (1997) Signalling through the Lipid Products of Phosphoinositide-3-OH Kinase. Nature, 387, 673-676. [Google Scholar] [CrossRef] [PubMed]
[16] Folkes, A.J., Ahmadi, K., Alderton, W.K., et al. (2008) The Identification of 2-(1H-indazol-4-yl)-6-(4-methanesul- fonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a Potent, Selective, Orally Bioavailable Inhibitor of Class I PI3 Kinase for the Treatment of Cancer. Journal of Medicinal Chemistry, 51, 5522-5532. [Google Scholar] [CrossRef] [PubMed]
[17] Burke, J.E. (2018) Structural Basis for Regulation of Phosphoinositide Kinases and Their Involvement in Human Disease. Molecular Cell, 71, 653-673. [Google Scholar] [CrossRef] [PubMed]
[18] Kriplani, N., Hermida, M.A., Brown, E.R., et al. (2015) Class IPI3-Kinases: Function and Evolution. Advances in Biological Regulation, 59, 53-64. [Google Scholar] [CrossRef] [PubMed]
[19] Bilanges, B., Posor, Y. and Vanhaesebroeck, B. (2019) PI3K Isoforms in Cell Signalling and Vesicle Trafficking. Nature Reviews Molecular Cell Biology, 20, 515-534. [Google Scholar] [CrossRef] [PubMed]
[20] Arcucci, S., Ramos-Delgado, F., Cayron, C., et al. (2021) Organ-ismal Roles for the PI3Kα and β Isoforms: Their Specificity, Redundancy or Cooperation Is Context-Dependent. Bio-chemical Journal, 478, 1199-1225. [Google Scholar] [CrossRef
[21] Gerstung, M., Jolly, C., Leshchiner, I., et al. (2020) The Evolutionary History of 2,658 Cancers. Nature, 578, 122-128. [Google Scholar] [CrossRef] [PubMed]
[22] He, Y., Sun, M.M., Zhang, G.G., et al. (2021) Targeting PI3K/Akt Signal Transduction for Cancer Therapy. Signal Transduction and Targeted Therapy, 6, 425. [Google Scholar] [CrossRef] [PubMed]
[23] Herman, S.E., Gordon, A.L., Wagner, A.J., et al. (2010) Phos-phatidylinositol 3-Kinase-δ Inhibitor CAL-101 Shows Promising Preclinical Activity in Chronic Lymphocytic Leukemia by Antagonizing Intrinsic and Extrinsic Cellular Survival Signals. Blood: The Journal of the American Society of Hema-tology, 116, 2078-2088. [Google Scholar] [CrossRef] [PubMed]
[24] Tsolakos, N., Durrant, T., Chessa, T., et al. (2018) Quantita-tion of Class IA PI3Ks in Mice Reveals p110-Free-p85s and Isoform-Selective Subunit Associations and Recruitment to Receptors. Proceedings of the National Academy of Sciences, 115, 12176-12181. [Google Scholar] [CrossRef] [PubMed]
[25] Mishra, R., Patel, H., Alanazi, S., et al. (2021) PI3K Inhibitors in Cancer: Clinical Implications and Adverse Effects. International Journal of Molecular Sciences, 22, Article No. 3464. [Google Scholar] [CrossRef] [PubMed]
[26] Braccini, L., Ciraolo, E., Campa, C.C., et al. (2015) PI3K-C2γ Is a Rab5 Effector Selectively Controlling Endosomal Akt2 Activation Downstream of Insulin Signalling. Nature Communications, 6, Article No. 7400. [Google Scholar] [CrossRef] [PubMed]
[27] Gulluni, F., Martini, M., De Santis, M.C., et al. (2017) Mitotic Spindle Assembly and Genomic Stability in Breast Cancer Require PI3K-C2α Scaffolding Function. Cancer Cell, 32, 444-459.e447. [Google Scholar] [CrossRef] [PubMed]
[28] Gulluni, F., De Santis, M.C., Margaria, J.P., et al. (2019) Class II PI3K Functions in Cell Biology and Disease. Trends in Cell Biology, 29, 339-359. [Google Scholar] [CrossRef] [PubMed]
[29] Marat, A.L. and Haucke, V. (2016) Phosphatidylinositol 3‐Phosphates—At the Interface between Cell Signalling and Membrane Traffic. The EMBO Journal, 35, 561-579. [Google Scholar] [CrossRef] [PubMed]
[30] O’Farrell, F., Lobert, V.H., Sneeggen, M., et al. (2017) Class III Phosphatidylinositol-3-OH Kinase Controls Epithelial Integrity through Endosomal LKB1 Regulation. Nature Cell Biol-ogy, 19, 1412-1423. [Google Scholar] [CrossRef] [PubMed]
[31] Stjepanovic, G., Baskaran, S., Lin, M.G., et al. (2017) Vps34 Kinase Domain Dynamics Regulate the Autophagic PI 3-Kinase Complex. Molecular Cell, 67, 528-534.e523. [Google Scholar] [CrossRef] [PubMed]
[32] Xu, Z., Han, X., Ou, D., et al. (2020) Targeting PI3K/AKT/mTOR-Mediated Autophagy for Tumor Therapy. Applied Microbiology and Biotechnology, 104, 575-587. [Google Scholar] [CrossRef] [PubMed]
[33] Ramaswamy, B., Lu, Y., Teng, K.-Y., et al. (2012) Hedgehog Signaling Is a Novel Therapeutic Target in Tamoxifen-Resistant Breast Cancer Aberrantly Activated by PI3K/AKT Pathway. Cancer Research, 72, 5048-5059. [Google Scholar] [CrossRef
[34] Hong, S., Zhang, H., Can, X., et al. (2009) Clinicopatho-logical Research and Expression of PTEN/PI3K/Akt Signaling Pathway in Non-Small Cell Lung Cancer. Chinese Jour-nal of Lung Cancer, 12, 889-892.
[35] Brennan, C.W., Verhaak, R.G., McKenna, A., et al. (2013) The Somatic Ge-nomic Landscape of Glioblastoma. Cell, 155, 462-477. [Google Scholar] [CrossRef] [PubMed]
[36] Mackay, A., Burford, A., Carvalho, D., et al. (2017) Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma. Cancer Cell, 32, 520-537.e5. [Google Scholar] [CrossRef] [PubMed]
[37] The Cancer Genome Atlas Network (2012) Comprehensive Molecular Portraits of Human Breast Tumours. Nature, 490, 61-70. [Google Scholar] [CrossRef] [PubMed]
[38] Akbani, R., Akdemir, K.C., Aksoy, B.A., et al. (2015) Genomic Classi-fication of Cutaneous Melanoma. Cell, 161, 1681-1696. [Google Scholar] [CrossRef] [PubMed]
[39] Thakur, A., Tawa, G.J., Henderson, M.J., et al. (2020) Design, Synthesis, and Biological Evaluation of Quinazolin-4-one-based hy-droxamic Acids as Dual PI3K/HDAC Inhibitors. Journal of Medicinal Chemistry, 63, 4256-4292. [Google Scholar] [CrossRef] [PubMed]
[40] Lee, Y.-R., Chen, M. and Pandolfi, P.P. (2018) The Functions and Regulation of the PTEN Tumour Suppressor: New Modes and Prospects. Nature Reviews Molecular Cell Biology, 19, 547-562. [Google Scholar] [CrossRef] [PubMed]
[41] Robbins, H.L. and Hague, A. (2016) The PI3K/Akt Pathway in Tumors of Endocrine Tissues. Frontiers in Endocrinology, 6, Article No. 188. [Google Scholar] [CrossRef] [PubMed]
[42] Courtney, K.D., Corcoran, R.B. and Engelman, J.A. (2010) The PI3K Pathway as Drug Target in Human Cancer. Journal of Clinical Oncology, 28, 1075-1083. [Google Scholar] [CrossRef
[43] Brana, I. and Siu, L.L. (2012) Clinical Development of Phosphati-dylinositol 3-Kinase Inhibitors for Cancer Treatment. BMC Medicine, 10, Article No. 161. [Google Scholar] [CrossRef] [PubMed]
[44] Sarbassov, D.D., Guertin, D.A., Ali, S.M., et al. (2005) Phos-phorylation and Regulation of Akt/PKB by the Rictor-mTOR Complex. Science, 307, 1098-1101. [Google Scholar] [CrossRef] [PubMed]