Targeting SHP2 as a promising strategy for cancer immunotherapy. (February 2020)

• Record Type: Journal Article
• Authors: Liu, Qianqian; Qu, Jiao; Zhao, Mingxia; Xu, Qiang; Sun, Yang
• Is Part Of: Pharmacological research. Volume 152(2020)
• Publication Date: 2020-02
• Subjects: SHP2 Src homology-2-containing protein tyrosine phosphatase 2 -- PTP protein tyrosine phosphatase -- ITSM immunoreceptor tyrosine-based switch motif -- ITAM immunoreceptor tyrosine-based activation motif -- ITIM immunoreceptor tyrosine-based inhibitory motif -- ZAP70 Zeta chain-associated protein kinase 70 -- PD-1 programmed death 1 -- CTLA-4 cytotoxic T-lymphocyte-associated antigen 4 -- BTLA B and the T lymphocyte attenuator -- TIGIT immunoreceptor tyrosine-based inhibitory motif domain -- TIM-3 the immunoglobulin domain and mucin domain 3 -- VISTA V-domain Ig suppressor of T cell activation -- LAG-3 lymphocyte activation gene 3 -- ITIM immunoreceptor tyrosine-based inhibitory motif -- AP-1 activator protein 1 -- NF-κB nuclear factor κB -- NFAT nuclear factor of activated T cells -- mTOR mammalian target of rapamycin -- CSF-1 colony-stimulating factor 1 -- CSF-1R CSF-1 receptor -- Grb2 growth factor receptor-bound protein 2 -- Gab2 Grb2-associated binding protein 2 -- SIRPα signal regulatory protein α -- Siglec-10 sialic-acid-binding Ig-like lectin 10 -- BCR B cell antigen receptor -- NK natural kill cell -- DC dendritic cell -- KIR killer cell Ig-like receptors -- RTK receptor-tyrosine kinase -- JAK Janus kinase -- STAT3 signal transducer and activator of transcription 3 -- IKK IκB kinase -- PHPS1 C-terminal Src kinas, phenylhydrazonopyrazolone sulfonate 1 -- NSCLC non-small cell lung cancer -- ESCC esophageal squamous cell cancer; SHP2 -- T lymphocyte -- Macrophage -- Tumor immunotherapy -- SHP2 inhibitor; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2019.104595
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Targeting SHP2 plays multiple roles in cancer. ① SHP2 is a critical regulator of RAS-MAPK pathway. SHP2i may inhibit cancers driven by RTK or KRAS alteration. ② SHP2 is a critical downstream effector for PD-1/PD-L1 and CD28 pathway. SHP2i may facilitate CD8 + cytotoxic activity. ③ SHP2 is a critical downstream effector for M-CSF/CSF-1R pathway. SHP2i may suppress the activities of TAM. In general, SHP2 inhibitors might target cancer cell, T lymphocyte and macrophage simultaneously, thereby exerting strong anti-tumor effects. Abstract: Src homology-2-containing protein tyrosine phosphatase 2 (SHP2) is a major phosphatase involved in several cellular processes. In recent years, SHP2 has been the focus of significant attention in human diseases, particular in cancer. Several studies have shown that SHP2 plays an important role in regulating immune cell functions in tumor microenvironment. A few clinical trials conducted using SHP2 allosteric inhibitors have shown remarkable anti-tumor benefits and good safety profiles. This review focuses on the current understanding of the regulation of SHP2 and highlights the vital roles of SHP2 in T lymphocytes, macrophages and cancer cells. It also summarizes the current development of SHP2 inhibitors as a promising strategy for cancer immunotherapy.