PI3K参与细胞生长、增殖等重要过程，在多种癌症中检测到PI3K的突变或信号的上调。目前已发现8个PI3K亚型，PI3K可分为三类，1类、2类和3类，其中1类和癌症相关，共包含4个亚型，2类和3类和膜运输相关，分别包含3个亚型和1个亚型。1类PI3K包含PI3Kα、PI3Kβ、PI3Kδ和PI3Kγ四个亚型，PI3K受到上游RTK、GPCR等信号的激活，可催化PIP3的生成，从而激活AKT/mTOR信号通路，激活细胞增殖与生长。

 

在癌症中，PI3Kα的突变和PI3Kβ/PI3Kδ/PI3Kγ的增强都是非常常见的。但是，PI3K的不同亚型之间，并非只是互相替代的冗余关系，而是各自承担不同的重要生理功能。PI3Kα可响应胰岛素信号，参与血糖调节，PI3Kβ在血小板调节中发挥重要作用，PI3Kδ调控T细胞发育和B细胞功能维持，而PI3Kγ则可通过巨噬细胞调节天然免疫。虽然在肿瘤中存在PI3K信号的增强，抑制肿瘤的PI3K信号可以有效抑制肿瘤，但PI3K对肿瘤的驱动作用本身较弱，且并非对所有人群有效，对于非肿瘤相关的PI3K的抑制也会造成较为严重的毒性。同时，PI3K处于复杂的信号网络调控之中，存在许多负反馈调节，也限制了PI3K抑制剂的疗效。

 

截至2018年，600个以上PI3K抑制剂结构被公开发表或出现在专利中，但仅有4个成功作为药物获批上市，且表现出不同程度的毒性和一般的疗效。未来，PI3K抑制剂的研发，还需要选择性更强的化合物，和对不同亚型间的选择性的精确调控，并且找到适合的适应症及用药人群。

 

 

参考资料：

1. Baselga, J., Im, S. A., Iwata, H., Cortes, J., De Laurentiis, M., Jiang, Z., . . . Campone, M. (2017). Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol, 18(7), 904-916. doi:10.1016/S1470-2045(17)30376-5

2. Dbouk, H. A., & Backer, J. M. (2010). A beta version of life: p110beta takes center stage. Oncotarget, 1(8), 729-733. doi:10.18632/oncotarget.101205

3. Garces, A. E., & Stocks, M. J. (2019). Class 1 PI3K Clinical Candidates and Recent Inhibitor Design Strategies: A Medicinal Chemistry Perspective. J Med Chem, 62(10), 4815-4850. doi:10.1021/acs.jmedchem.8b01492

4. Feng, Y., Cu, X., & Xin, M. (2019). PI3Kdelta inhibitors for the treatment of cancer: a patent review (2015-present). Expert Opin Ther Pat, 29(12), 925-941. doi:10.1080/13543776.2019.1687685

5. Garces, A. E., & Stocks, M. J. (2019). Class 1 PI3K Clinical Candidates and Recent Inhibitor Design Strategies: A Medicinal Chemistry Perspective. J Med Chem, 62(10), 4815-4850. doi:10.1021/acs.jmedchem.8b01492

6. Gratacap, M. P., Guillermet-Guibert, J., Martin, V., Chicanne, G., Tronchere, H., Gaits-Iacovoni, F., & Payrastre, B. (2011). Regulation and roles of PI3Kbeta, a major actor in platelet signaling and functions. Adv Enzyme Regul, 51(1), 106-116. doi:10.1016/j.advenzreg.2010.09.011

7. Haddadi, N., Lin, Y., Travis, G., Simpson, A. M., Nassif, N. T., & McGowan, E. M. (2018). PTEN/PTENP1: 'Regulating the regulator of RTK-dependent PI3K/Akt signalling', new targets for cancer therapy. Mol Cancer, 17(1), 37. doi:10.1186/s12943-018-0803-3

8. Hanker, A. B., Kaklamani, V., & Arteaga, C. L. (2019). Challenges for the Clinical Development of PI3K Inhibitors: Strategies to Improve Their Impact in Solid Tumors. Cancer Discov, 9(4), 482-491. doi:10.1158/2159-8290.CD-18-1175

9. Lim, E. L., & Okkenhaug, K. (2019). Phosphoinositide 3-kinase delta is a regulatory T-cell target in cancer immunotherapy. Immunology, 157(3), 210-218. doi:10.1111/imm.13082

10. Liu, S., Knapp, S., & Ahmed, A. A. (2014). The structural basis of PI3K cancer mutations: from mechanism to therapy. Cancer Res, 74(3), 641-646. doi:10.1158/0008-5472.CAN-13-2319

11. Liu, P., Cheng, H., Roberts, T. M., & Zhao, J. J. (2009). Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov, 8(8), 627-644. doi:10.1038/nrd2926

12. Lucas, C. L., Chandra, A., Nejentsev, S., Condliffe, A. M., & Okkenhaug, K. (2016). PI3Kdelta and primary immunodeficiencies. Nat Rev Immunol, 16(11), 702-714. doi:10.1038/nri.2016.93

13. Mayer, I. A., Abramson, V. G., Formisano, L., Balko, J. M., Estrada, M. V., Sanders, M. E., . . . Arteaga, C. L. (2017). A Phase Ib Study of Alpelisib (BYL719), a PI3Kalpha-Specific Inhibitor, with Letrozole in ER+/HER2- Metastatic Breast Cancer. Clin Cancer Res, 23(1), 26-34. doi:10.1158/1078-0432.CCR-16-0134

14. Ilic, N., & Roberts, T. M. (2010). Comparing the roles of the p110alpha and p110beta isoforms of PI3K in signaling and cancer. Curr Top Microbiol Immunol, 347, 55-77. doi:10.1007/82_2010_63

15. Samuels, Y., Wang, Z., Bardelli, A., Silliman, N., Ptak, J., Szabo, S., . . . Velculescu, V. E. (2004). High frequency of mutations of the PIK3CA gene in human cancers. Science, 304(5670), 554. doi:10.1126/science.1096502

16. Okkenhaug, K., Graupera, M., & Vanhaesebroeck, B. (2016). Targeting PI3K in Cancer: Impact on Tumor Cells, Their Protective Stroma, Angiogenesis, and Immunotherapy. Cancer Discov, 6(10), 1090-1105. doi:10.1158/2159-8290.CD-16-0716

17. Solinas, G., & Becattini, B. (2017). The role of PI3Kgamma in metabolism and macrophage activation. Oncotarget, 8(63), 106145-106146. doi:10.18632/oncotarget.22068

18. Stratikopoulos, E. E., Kiess, N., Szabolcs, M., Pegno, S., Kakit, C., Wu, X., . . . Parsons, R. (2019). Mouse ER+/PIK3CA(H1047R) breast cancers caused by exogenous estrogen are heterogeneously dependent on estrogen and undergo BIM-dependent apoptosis with BH3 and PI3K agents. Oncogene, 38(1), 47-59. doi:10.1038/s41388-018-0436-4

19. Thorpe, L. M., Yuzugullu, H., & Zhao, J. J. (2015). PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting. Nature Reviews Cancer, 15(1), 7-24. doi:10.1038/nrc3860

20. Vanhaesebroeck, B., Whitehead, M. A., & Pineiro, R. (2016). Molecules in medicine mini-review: isoforms of PI3K in biology and disease. J Mol Med (Berl), 94(1), 5-11. doi:10.1007/s00109-015-1352-5

21. Yang, J., Nie, J., Ma, X., Wei, Y., Peng, Y., & Wei, X. (2019). Targeting PI3K in cancer: mechanisms and advances in clinical trials. Mol Cancer, 18(1), 26. doi:10.1186/s12943-019-0954-x