ACK1及其小分子抑制剂在肿瘤发生发展中的研究进展
Research Progress on ACK1 and Its Small Molecule Inhibitors in Tumor Occurrence and Development
DOI: 10.12677/acm.2024.1451598, PDF,    科研立项经费支持
作者: 刘轩宇, 黄家辉, 廖启琛, 程 晴, 陈吴京津, 张 茹, 李新齐, 董炜昊：济宁医学院临床医学院，山东 济宁；夏 帅*：济宁医学院基础医学院，山东 济宁
关键词: ACK1；肿瘤；非受体酪氨酸激酶；小分子抑制剂；ACK1； Tumor； Non-Receptor Tyrosine Kinase； Small Molecule Inhibitors
摘要: ACK1 (活化的Cdc42相关激酶1)属于非受体酪氨酸激酶，是小G蛋白Cdc42的效应蛋白，可以被多种细胞外生长因子如EGF、PDGF和TGF-β激活。在癌症中，ACK1的基因扩增和过表达与肺癌、卵巢癌和前列腺癌等多种恶性肿瘤的不良预后和转移表型相关。针对ACK1的研究表明，通过开发针对ACK1的高效选择性小分子抑制剂，可为癌症治疗提供新的候选药物。本综述对ACK1激活方式及其在肿瘤发生发展中的作用进行了扼要描述，阐述了ACK1的小分子抑制剂的最新研究进展，并讨论和展望了这些抑制剂在临床前研究中的应用潜力。
Abstract: ACK1 (activated Cdc42-associated kinase 1) is a non-receptor tyrosine kinase and an effector protein for the small G protein Cdc42, which can be activated by various extracellular growth factors such as EGF, PDGF, and TGF-β. In cancer, the amplification and over-expression of ACK1 gene are associated with poor prognosis and metastatic phenotype in various malignant tumors such as lung cancer, ovarian cancer, and prostate cancer. Research on ACK1 suggests that developing efficient and selective small molecule inhibitors targeting ACK1 may provide new candidate drugs for cancer treatment. This review provides a brief description of the activation mode of ACK1 and its role in tumor development, elucidates the latest research progress on small molecule inhibitors of ACK1, and discusses and prospects the potential application of these inhibitors in preclinical research.
文章引用：刘轩宇, 黄家辉, 廖启琛, 程晴, 陈吴京津, 张茹, 李新齐, 董炜昊, 夏帅. ACK1及其小分子抑制剂在肿瘤发生发展中的研究进展[J]. 临床医学进展, 2024, 14(5): 1633-1641. https://doi.org/10.12677/acm.2024.1451598

参考文献

[1] Xu, S.-H., Huang, J.-Z., Chen, M., et al. (2017) Amplification of ACK1 Promotes Gastric Tumorigenesis via ECD-Dependent p53 Ubiquitination Degradation. Oncotarget, 8, 12705-12716. [Google Scholar] [CrossRef] [PubMed]
[2] Li, Z.N., Powell, C.E., Groendyke, B.J., et al. (2020) Discovery of a Series of Benzopyrimidodiazepinone TNK2 Inhibitors via Scaffold Morphing. Bioorganic & Medicinal Chemistry Letters, 30, Article 127456. [Google Scholar] [CrossRef] [PubMed]
[3] Mahajan, K. and Mahajan, N.P. (2010) Shepherding AKT and Androgen Receptor by ACK1 Tyrosine Kinase. Journal of Cellular Physiology, 224, 327-333. [Google Scholar] [CrossRef] [PubMed]
[4] Prieto-Echagüe, V., Gucwa, A., Brown, D.A., et al. (2010) Regulation of ACK1 Localization and Activity by the Amino-Terminal SAM Domain. BMC Biochemistry, 11, Article No. 42. [Google Scholar] [CrossRef] [PubMed]
[5] Prieto-Echagüe, V., Gucwa, A., Craddock, B.P., et al. (2010) Cancer-Associated Mutations Activate the Nonreceptor Tyrosine Kinase ACK1. The Journal of Biological Chemistry, 285, 10605-10615. [Google Scholar] [CrossRef] 
[6] Lin, Q., Wang, J., Childress, C., et al. (2012) The Activation Mechanism of ACK1 (Activated Cdc42-Associated Tyrosine Kinase 1). The Biochemical Journal, 445, 255-264. [Google Scholar] [CrossRef] 
[7] Fox, M., Mott, H.R. and Owen, D. (2020) Class IA PI3K Regulatory Subunits: p110-Independent Roles and Structures. Biochemical Society Transactions, 48, 1397-1417. [Google Scholar] [CrossRef] 
[8] Fox, M., Crafter, C. and Owen, D. (2019) The Non-Receptor Tyrosine Kinase ACK: Regulatory Mechanisms, Signalling Pathways and Opportunities for attACKing Cancer. Biochemical Society Transactions, 47, 1715-1731. [Google Scholar] [CrossRef] 
[9] Geering, B., Cutillas, P.R., Nock, G., et al. (2007) Class IA Phosphoinositide 3-Kinases Are Obligate p85-p110 Heterodimers. Proceedings of the National Academy of Sciences of the United States of America, 104, 7809-7814. [Google Scholar] [CrossRef] [PubMed]
[10] Fu, Z., Aronoff-Spencer, E., Backer, J.M., et al. (2003) The Structure of the Inter-SH2 Domain of Class IA Phosphoinositide 3-Kinase Determined by Site-Directed Spin Labeling EPR and Homology Modeling. Proceedings of the National Academy of Sciences of the United States of America, 100, 3275-3280. [Google Scholar] [CrossRef] [PubMed]
[11] Wang, G.Q., Zhang, M.Z., Jang, H.B., et al. (2018) Interaction of Calmodulin with the cSH2 Domain of the p85 Regulatory Subunit. Biochemistry, 57, 1917-1928. [Google Scholar] [CrossRef] [PubMed]
[12] Nur-E-Kamal, A., Zhang, A., Keenan, S.M., et al. (2005) Requirement of Activated Cdc42-Associated Kinase for Survival of v-Ras-Transformed Mammalian Cells. Molecular Cancer Research, 3, 297-305. [Google Scholar] [CrossRef] 
[13] Cox, K.J., Shomin, C.D. and Ghosh, I. (2011) Tinkering Outside the Kinase ATP Box: Allosteric (Type IV) and Bivalent (Type V) Inhibitors of Protein Kinases. Future Medicinal Chemistry, 3, 29-43. [Google Scholar] [CrossRef] [PubMed]
[14] Lawrence, H.R., Mahajan, K., Luo, Y., et al. (2015) Development of Novel ACK1/TNK2 Inhibitors Using a Fragment-Based Approach. Journal of Medicinal Chemistry, 58, 2746-2763. [Google Scholar] [CrossRef] [PubMed]
[15] Mahajan, K. and Mahajan, N.P. (2012) PI3K-Independent AKT Activation in Cancers: A Treasure Trove for Novel Therapeutics. Journal of Cellular Physiology, 227, 3178-3184. [Google Scholar] [CrossRef] [PubMed]
[16] Mahajan, K. and Mahajan, N.P. (2013) ACK1 Tyrosine Kinase: Targeted Inhibition to Block Cancer Cell Proliferation. Cancer Letters, 338, 185-192. [Google Scholar] [CrossRef] [PubMed]
[17] Zhang, N., Zeng, X., Sun, C., et al. (2019) LncRNA LINC00963 Promotes Tumorigenesis and Radioresistance in Breast Cancer by Sponging miR-324-3p and Inducing ACK1 Expression. Molecular Therapy Nucleic Acids, 18, 871-881. [Google Scholar] [CrossRef] [PubMed]
[18] Sawant, M., Wilson, A., Sridaran, D., et al. (2023) Epigenetic Reprogramming of Cell Cycle Genes by ACK1 Promotes Breast Cancer Resistance to CDK4/6 Inhibitor. Oncogene, 42, 2263-2277. [Google Scholar] [CrossRef] [PubMed]
[19] Buchwald, M., Pietschmann, K., Brand, P., et al. (2013) SIAH Ubiquitin Ligases Target the Nonreceptor Tyrosine Kinase ACK1 for Ubiquitinylation and Proteasomal Degradation. Oncogene, 32, 4913-4920. [Google Scholar] [CrossRef] [PubMed]
[20] Karaca, M., Liu, Y., Zhang, Z., et al. (2015) Mutation of Androgen Receptor N-Terminal Phosphorylation Site Tyr-267 Leads to Inhibition of Nuclear Translocation and DNA Binding. PLOS ONE, 10, e0126270. [Google Scholar] [CrossRef] [PubMed]
[21] Mahajan, K., Coppola, D., Challa, S., et al. (2010) ACK1 Mediated AKT/PKB Tyrosine 176 Phosphorylation Regulates Its Activation. PLOS ONE, 5, e9646. [Google Scholar] [CrossRef] [PubMed]
[22] Brandao, R., Kwa, M.Q., Yarden, Y., et al. (2021) ACK1 Is Dispensable for Development, Skin Tumor Formation, and Breast Cancer Cell Proliferation. FEBS Open Bio, 11, 1579-1592. [Google Scholar] [CrossRef] [PubMed]
[23] Mahajan, K., Malla, P., Lawrence, H.R., et al. (2017) ACK1/TNK2 Regulates Histone H4 Tyr88-Phosphorylation and AR Gene Expression in Castration-Resistant Prostate Cancer. Cancer Cell, 31, 790-803. [Google Scholar] [CrossRef] [PubMed]
[24] Mahajan, N.P., Whang, Y.E., Mohler, J.L., et al. (2005) Activated Tyrosine Kinase ACK1 Promotes Prostate Tumorigenesis: Role of ACK1 in Polyubiquitination of Tumor Suppressor Wwox. Cancer Research, 65, 10514-10523. [Google Scholar] [CrossRef] 
[25] Xie, B., Zen, Q., Wang, X., et al. (2015) ACK1 Promotes Hepatocellular Carcinoma Progression via Downregulating WWOX and Activating AKT Signaling. International Journal of Oncology, 46, 2057-2066. [Google Scholar] [CrossRef] [PubMed]
[26] Sridaran, D., Chouhan, S., Mahajan, K., et al. (2022) Inhibiting ACK1-Mediated Phosphorylation of C-Terminal Src Kinase Counteracts Prostate Cancer Immune Checkpoint Blockade Resistance. Nature Communications, 13, Article No. 6929. [Google Scholar] [CrossRef] [PubMed]
[27] Mahajan, N.P., Liu, Y., Majumder, S., et al. (2007) Activated Cdc42-Associated Kinase ACK1 Promotes Prostate Cancer Progression via Androgen Receptor Tyrosine Phosphorylation. Proceedings of the National Academy of Sciences of the United States of America, 104, 8438-8443. [Google Scholar] [CrossRef] [PubMed]
[28] De Silva, D., Zhang, Z., Liu, Y., et al. (2019) Interaction between Androgen Receptor and Coregulator SLIRP Is Regulated by ACK1 Tyrosine Kinase and Androgen. Scientific Reports, 9, Article No. 18637. [Google Scholar] [CrossRef] [PubMed]
[29] Chouhan, S., Sawant, M., Weimholt, C., et al. (2023) TNK2/ACK1-Mediated Phosphorylation of ATP5F1A (ATP Synthase F1 Subunit Alpha) Selectively Augments Survival of Prostate Cancer While Engendering Mitochondrial Vulnerability. Autophagy, 19, 1000-1025. [Google Scholar] [CrossRef] [PubMed]
[30] Xu, S.-H., Huang, J.-Z., Xu, M.-L., et al. (2015) ACK1 Promotes Gastric Cancer Epithelial-Mesenchymal Transition and Metastasis through AKT-POU2F1-ECD Signalling. The Journal of Pathology, 236, 175-185. [Google Scholar] [CrossRef] [PubMed]
[31] Chua, B.T., Lim, S.J., Tham, S.C., et al. (2010) Somatic Mutation in the ACK1 Ubiquitin Association Domain Enhances Oncogenic Signaling through EGFR Regulation in Renal Cancer Derived Cells. Molecular Oncology, 4, 323-334. [Google Scholar] [CrossRef] [PubMed]
[32] Zhu, J., Liu, Y., Ao, H., et al. (2020) Comprehensive Analysis of the Immune Implication of ACK1 Gene in Non-Small Cell Lung Cancer. Frontiers in Oncology, 10, Article 1132. [Google Scholar] [CrossRef] [PubMed]
[33] Zhu, J.H., Liu, Y., Zhao, M., et al. (2021) Identification of Downstream Signaling Cascades of ACK1 and Prognostic Classifiers in Non-Small Cell Lung Cancer. Aging, 13, 4482-4502. [Google Scholar] [CrossRef] [PubMed]
[34] Zhang, A.Q., Zhang, R.X., Yang, Z.M., et al. (2021) TNK2 Promoted Esophageal Cancer Progression via Activating Egfr-Akt Signaling. Journal of Clinical Laboratory Analysis, 35, e23700. [Google Scholar] [CrossRef] [PubMed]
[35] Yu, X.J., Liu, J., Qiu, H.W., et al. (2021) Combined Inhibition of ACK1 and AKT Shows Potential toward Targeted Therapy against KRAS-Mutant Non-Small-Cell Lung Cancer. Bosnian Journal of Basic Medical Sciences, 21, 198-207. [Google Scholar] [CrossRef] [PubMed]
[36] Gu, J., Qian, L., Zhang, G., et al. (2020) Inhibition of ACK1 Delays and Overcomes Acquired Resistance of EGFR Mutant NSCLC Cells to the Third Generation EGFR Inhibitor, Osimertinib. Lung Cancer, 150, 26-35. [Google Scholar] [CrossRef] [PubMed]
[37] Mahajan, K., Coppola, D., Chen, Y.A., et al. (2012) ACK1 Tyrosine Kinase Activation Correlates with Pancreatic Cancer Progression. The American Journal of Pathology, 180, 1386-1393. [Google Scholar] [CrossRef] [PubMed]
[38] Kong, D., Li, G., Yang, Z., et al. (2022) Identification of an ACK1/TNK2-Based Prognostic Signature for Colon Cancer to Predict Survival and Inflammatory Landscapes. BMC Cancer, 22, Article No. 84. [Google Scholar] [CrossRef] [PubMed]
[39] 李芊. 新型选择性ACK1抑制剂的设计合成及抗肿瘤活性研究[D]: [硕士学位论文]. 广州: 暨南大学, 2022.
[40] Wu, X., Zahari, M.S., Renuse, S., et al. (2017) The Non-Receptor Tyrosine Kinase TNK2/ACK1 Is a Novel Therapeutic Target in Triple Negative Breast Cancer. Oncotarget, 8, 2971-2983. [Google Scholar] [CrossRef] [PubMed]
[41] Mahajan, K., Challa, S., Coppola, D., et al. (2010) Effect of ACK1 Tyrosine Kinase Inhibitor on Ligand-Independent Androgen Receptor Activity. The Prostate, 70, 1274-1285. [Google Scholar] [CrossRef] [PubMed]
[42] Mahajan, K., Coppola, D., Rawal, B., et al. (2012) ACK1-Mediated Androgen Receptor Phosphorylation Modulates Radiation Resistance in Castration-Resistant Prostate Cancer. The Journal of Biological Chemistry, 287, 22112-22122. [Google Scholar] [CrossRef] 
[43] Li, J., Rix, U., Fang, B., et al. (2010) A Chemical and Phosphoproteomic Characterization of Dasatinib Action in Lung Cancer. Nature Chemical Biology, 6, 291-299. [Google Scholar] [CrossRef] [PubMed]
[44] Liu, Y., Karaca, M., Zhang, Z., et al. (2010) Dasatinib Inhibits Site-Specific Tyrosine Phosphorylation of Androgen Receptor by ACK1 and Src Kinases. Oncogene, 29, 3208-3216. [Google Scholar] [CrossRef] [PubMed]
[45] Tan, D.S., Haaland, B., Gan, J.M., et al. (2014) Bosutinib Inhibits Migration and Invasion via ACK1 in KRAS Mutant Non-Small Cell Lung Cancer. Molecular Cancer, 13, Article No. 13. [Google Scholar] [CrossRef] [PubMed]
[46] Wang, A.X., Shuai, W., Wu, C.Y., et al. (2024) Design, Synthesis, and Biological Evaluation of Dual Inhibitors of EGFRL858R/T790M/ACK1 to Overcome Osimertinib Resistance in Nonsmall Cell Lung Cancers. Journal of Medicinal Chemistry, 67, 2777-2801. [Google Scholar] [CrossRef] [PubMed]

为你推荐