Technology/ Title:MAP4K3 is a therapeutic target for cancer and IL-17A-mediated autoimmune disease

Our team has identified MAP4K3 (GLK), MAP4K1 (HPK1), and MAP4K4 (HGK) in the 1990s.

We reported that MAP4K3 (GLK) overexpression is correlated with human autoimmune diseases and cancer recurrence. Using MAP4K3-deficient and MAP4K3 transgenic mice, we demonstrated that MAP4K3 overexpression selectively induces IL-17A overproduction through AhR-RORγt complex in T cells, leading to autoimmune responses. Our findings indicate that MAP4K3 is a therapeutic target for autoimmune disease, cancer, and IL-17A-mediated disease. We further showed proof of concept by treatment of GLK inhibitors in mouse disease models.

Our team also demonstrated that HPK1 (MAP4K1) is a negative regulator of T-cell activation in 2007. Based on our finding, at least 10 companies have filed 23 patents on HPK1 inhibitors (plus anti-PD1) for cancer immunotherapy.

2011
Chuang, H.C., J.L. Lan, D.Y. Chen, C.Y. Yang, Y.M. Chen, J.P. Li, C.Y. Huang, P.E. Liu, X. Wang, and T.-H. Tan. 2011. The kinase GLK controls autoimmunity and NF-κB signaling by activating the kinase PKC-θ in T cells. Nature Immunology, 12:1113-1118.

2018
Chuang HC, CY Tsai, CH Hsueh and T.-H. Tan. 2018. GLK-IKKβ signaling induces dimerization and translocation of the AhR-RORγt complex in IL-17A induction and autoimmune disease. Science Advances, 4: eaat5401.

2007
Shui, J.-W., J.S. Boomer, J. Han, J. Xu, G.A. Dement, G. Zhou, and T.-H. Tan. 2007. HPK1 negatively regulates T-cell receptor signaling and T-cell-mediated immune responses. Nature Immunology, 8:84-91.