Activating Mutation of SHP2 Establishes a Tumorigenic Phonotype Through Cell-Autonomous and Non-Cell-Autonomous Mechanisms

Dong, Lei; Han, Da Woon; Meng, Xinyi; Xu, Mengchuan; Zheng, Chuwen; Qin, Xia

doi:10.3389/fcell.2021.630712

Cited by 13 publications

(14 citation statements)

References 114 publications

(73 reference statements)

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“…Src homology-2 domain-containing protein tyrosine phosphatase (SHP2) is a multifunctional tumorigenic protein with a central role in the survival, proliferation, metastasis, and drug resistance of tumor cells [ 91 , 92 , 93 , 94 ]. Recent studies have uncovered the effect of SHP2 on T-cell exhaustion in a tumor microenvironment [ 95 , 96 ].…”

Section: Small-molecule Protacs Targeting Pd-1/pd-l1 Checkpoint Signa...mentioning

confidence: 99%

Small-Molecule PROTACs for Cancer Immunotherapy

Liu¹,

Zhang²,

Xiang³

et al. 2022

Molecules

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Unsatisfactory physicochemical properties of macromolecular drugs seriously hinder their application in tumor immunotherapy. However, these problems can be effectively solved by small-molecule compounds. In the promising field of small-molecule drug development, proteolysis targeting chimera (PROTAC) offers a Cancer Patients. Bosn. J. Basic novel mode of action in the interactions between small molecules and therapeutic targets (mainly proteins). This revolutionary technology has shown considerable impact on several proteins related to tumor survival but is rarely exploited in proteins associated with immuno-oncology up until now. This review attempts to comprehensively summarize the well-studied and less-developed immunological targets available for PROTAC technology, as well as some targets to be explored, aiming to provide more options and opportunities for the development of small-molecule-based tumor immunotherapy. In addition, some novel directions that can magnify and broaden the protein degradation efficiency are mentioned to improve PROTAC design in the future.

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Section: Small-molecule Protacs Targeting Pd-1/pd-l1 Checkpoint Signa...mentioning

confidence: 99%

Small-Molecule PROTACs for Cancer Immunotherapy

Liu¹,

Zhang²,

Xiang³

et al. 2022

Molecules

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“…The Src homology 2 domain-containing phosphatase 2 (SHP2) belongs to the non-receptor protein-tyrosine phosphatase family and exerts important functions in cell survival, proliferation, migration, and differentiation in many tissues. Mutations within the Ptpn11 gene locus encoding SHP2 promote tumor progression and have been associated with Noonan syndrome, juvenile myelomonocytic leukemia (JMML) ( 1 , 2 ) and various other cancers ( 3 , 4 ). Enhanced activation of the Ras/Erk signaling pathway downstream of several growth factor receptors appears to be responsible for tumorigenesis induced by Ptpn11 gain-of-function mutations ( 5 ).…”

Section: Introductionmentioning

confidence: 99%

T cell-specific constitutive active SHP2 enhances T cell memory formation and reduces T cell activation

et al. 2022

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Upon antigen recognition by the T cell receptor (TCR), a complex signaling network orchestrated by protein-tyrosine kinases (PTKs) and protein-tyrosine phosphatases (PTPs) regulates the transmission of the extracellular signal to the nucleus. The role of the PTPs Src-homology 2 (SH2) domain-containing phosphatase 1 (SHP1, Ptpn6) and Src-homology 2 (SH2) domain-containing phosphatase 2 (SHP2, Ptpn11) have been studied in various cell types including T cells. Whereas SHP1 acts as an essential negative regulator of the proximal steps in T cell signalling, the role of SHP2 in T cell activation is still a matter of debate. Here, we analyzed the role of the constitutively active SHP2-D61Y-mutant in T cell activation using knock-in mice expressing the mutant form Ptpn11D61Y in T cells. We observed reduced numbers of CD8+ and increased numbers of CD4+ T cells in the bone marrow and spleen of young and aged SHP2-D61Y-mutant mice as well as in Influenza A Virus (IAV)-infected mice compared to controls. In addition, we found elevated frequencies of effector memory CD8+ T cells and an upregulation of the programmed cell death protein 1 (PD-1)-receptor on both CD4+ and CD8+ T cells. Functional analysis of SHP2-D61Y-mutated T cells revealed an induction of late apoptosis/necrosis, a reduced proliferation and altered signaling upon TCR stimulation. However, the ability of D61Y-mutant mice to clear viral infection was not affected. In conclusion, our data indicate an important regulatory role of SHP2 in T cell function, where the effect is determined by the kinetics of SHP2 phosphatase activity and differs in the presence of the permanently active and the temporally regulated phosphatase. Due to interaction of SHP2 with the PD-1-receptor targeting the protein-tyrosine phosphatase might be a valuable tool to enhance T cell activities in immunotherapy.

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“…SHP2 has been previously proposed as an important regulator in breast tumor progression with therapeutic potential [16]. Inhibiting SHP2 in breast cancer was correlated with extending the survival of tumor-bearing mice and suppressing cell proliferation [23].…”

Section: Compounds Inhibit Breast Cancer Cells' Proliferation and Via...mentioning

confidence: 99%

“…Therefore, the development of small-molecule inhibitors of SHP2 may provide the opportunity to inhibit oncogenic signaling in breast cells. Many synthetic compounds have shown an inhibitory effect on SHP2 [16], by targeting the catalytic site (e.g., thiazolidinone derivatives and NSC 87877) [17] or the allosteric site (e.g., SHP099) [18]. Furthermore, SHP2 inhibition and the combination of SHP2 and MEK or ERK inhibitors, were recently found to enhance antitumor efficacy in different types of cancer [16].…”

Section: Introductionmentioning

confidence: 99%

The Discovery of Potent SHP2 Inhibitors with Anti-Proliferative Activity in Breast Cancer Cell Lines

Ghemrawi

Khair

Hasan

et al. 2022

IJMS

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Despite available treatments, breast cancer is the leading cause of cancer-related death. Knowing that the tyrosine phosphatase SHP2 is a regulator in tumorigenesis, developing inhibitors of SHP2 in breast cells is crucial. Our study investigated the effects of new compounds, purchased from NSC, on the phosphatase activity of SHP2 and the modulation of breast cancer cell lines’ proliferation and viability. A combined ligand-based and structure-based virtual screening protocol was validated, then performed, against SHP2 active site. Top ranked compounds were tested via SHP2 enzymatic assay, followed by measuring IC50 values. Subsequently, hits were tested for their anti-breast cancer viability and proliferative activity. Our experiments identified three compounds 13030, 24198, and 57774 as SHP2 inhibitors, with IC50 values in micromolar levels and considerable selectivity over the analogous enzyme SHP1. Long MD simulations of 500 ns showed a very promising binding mode in the SHP2 catalytic pocket. Furthermore, these compounds significantly reduced MCF-7 breast cancer cells’ proliferation and viability. Interestingly, two of our hits can have acridine or phenoxazine cyclic system known to intercalate in ds DNA. Therefore, our novel approach led to the discovery of SHP2 inhibitors, which could act as a starting point in the future for clinically useful anticancer agents.

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Activating Mutation of SHP2 Establishes a Tumorigenic Phonotype Through Cell-Autonomous and Non-Cell-Autonomous Mechanisms

Cited by 13 publications

References 114 publications

Small-Molecule PROTACs for Cancer Immunotherapy

Small-Molecule PROTACs for Cancer Immunotherapy

T cell-specific constitutive active SHP2 enhances T cell memory formation and reduces T cell activation

The Discovery of Potent SHP2 Inhibitors with Anti-Proliferative Activity in Breast Cancer Cell Lines

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