Tyrosine phosphatase SHP2 is a promising drug target in cancer immunotherapy due to its bidirectional role in both tumor growth promotion and T-cell inactivation. Its allosteric inhibitor SHP099 is known to inhibit ca...Tyrosine phosphatase SHP2 is a promising drug target in cancer immunotherapy due to its bidirectional role in both tumor growth promotion and T-cell inactivation. Its allosteric inhibitor SHP099 is known to inhibit cancer cell growth both in vitro and in vivo. However, whether SHP099-mediated SHP2 inhibition retards tumor growth in vivo via anti-tumor immunity remains elusive. To address this, a CT-26 colon cancer xenograft model was established in mice since this cell line is insensitive to SHP099.Consequently, SHP099 minimally affected CT-26 tumor growth in immuno-deficient nude mice, but significantly decreased the tumor burden in CT-26 tumor-bearing mice with intact immune system.SHP099 augmented anti-tumor immunity, as shown by the elevated proportion of CD8tIFN-γtT cells and the upregulation of cytotoxic T-cell related genes including Granzyme B andPerforin, which decreased the tumor load. In addition, tumor growth in mice with SHP2-deficient T-cells was markedly slowed down because of enhanced anti-tumor responses. Finally, the combination of SHP099 and antiPD-1 antibody showed a higher therapeutic efficacy than either monotherapy in controlling tumor growthin two colon cancer xenograft models, indicating that these agents complement each other. Our study suggests that SHP2 inhibitor SHP099 is a promising candidate drug for cancer immunotherapy.展开更多
Chronic infection with Helicobacter pylori cagA-positive strains is the strongest risk factor for gastric cancer.The cagA gene product,CagA,is delivered into gastric epithelial cells via the bacterial type IV secretio...Chronic infection with Helicobacter pylori cagA-positive strains is the strongest risk factor for gastric cancer.The cagA gene product,CagA,is delivered into gastric epithelial cells via the bacterial type IV secretion system.Delivered CagA then undergoes tyrosine phosphorylation at the Glu-Pro-Ile-Tyr-Ala(EPIYA)motifs in its C-terminal region and acts as an oncogenic scaffold protein that physically interacts with multiple host signaling proteins in both tyrosine phosphorylation-dependent and-independent manners.Analysis of CagA using in vitro cultured gastric epithelial cells has indicated that the nonphysiological scaffolding actions of CagA cell-autonomously promote the malignant transformation of the cells by endowing the cells with multiple phenotypic cancer hallmarks:sustained proliferation,evasion of growth suppressors,invasiveness,resistance to cell death,and genomic instability.Transgenic expression of CagA in mice leads to in vivo oncogenic action of CagA without any overt inflammation.The in vivo oncogenic activity of CagA is further potentiated in the presence of chronic inflammation.Since Helicobacter pylori infection triggers a proinflammatory response in host cells,a feedforward stimulation loop that augments the oncogenic actions of CagA and inflammation is created in CagA-injected gastric mucosa.Given that Helicobacter pylori is no longer colonized in established gastric cancer lesions,the multistep nature of gastric cancer development should include a“hit-and-run”process of CagA action.Thus,acquisition of genetic and epigenetic alterations that compensate for CagA-directed cancer hallmarks may be required for completion of the“hit-and-run”process of gastric carcinogenesis.展开更多
Objective:The tyrosine phosphatase SHP2 has a dual role in cancer initiation and progression in a tissue type-dependent manner.Several studies have linked SHP2 to the aggressive behavior of breast cancer cells and poo...Objective:The tyrosine phosphatase SHP2 has a dual role in cancer initiation and progression in a tissue type-dependent manner.Several studies have linked SHP2 to the aggressive behavior of breast cancer cells and poorer outcomes in people with cancer.Nevertheless,the mechanistic details of how SHP2 promotes breast cancer progression remain largely undefined.Methods:The relationship between SHP2 expression and the prognosis of patients with breast cancer was investigated by using the TCGA and GEO databases.The expression of SHP2 in breast cancer tissues was analyzed by immunohistochemistry.CRISPR/Cas9 technology was used to generate SHP2-knockout breast cancer cells.Cell-counting kit-8,colony formation,cell cycle,and EdU incorporation assays,as well as a tumor xenograft model were used to examine the function of SHP2 in breast cancer proliferation.Quantitative RT-PCR,western blotting,immunofluorescence staining,and ubiquitination assays were used to explore the molecular mechanism through which SHP2 regulates breast cancer proliferation.Results:High SHP2 expression is correlated with poor prognosis in patients with breast cancer.SHP2 is required for the proliferation of breast cancer cellsin vitro and tumor growthin vivo through regulation of Cyclin D1 abundance,thereby accelerating cell cycle progression.Notably,SHP2 modulates the ubiquitin–proteasome-dependent degradation of Cyclin D1viathe PI3K/AKT/GSK3βsignaling pathway.SHP2 knockout attenuates the activation of PI3K/AKT signaling and causes the dephosphorylation and resultant activation of GSK3β.GSK3βthen mediates phosphorylation of Cyclin D1 at threonine 286,thereby promoting the translocation of Cyclin D1 from the nucleus to the cytoplasm and facilitating Cyclin D1 degradation through the ubiquitin–proteasome system.Conclusions:Our study uncovered the mechanism through which SHP2 regulates breast cancer proliferation.SHP2 may therefore potentially serve as a therapeutic target for breast cancer.展开更多
Src homology containing protein tyrosine phosphatase 2(SHP2)represents a noteworthy target for various diseases,serving as a well-known oncogenic phosphatase in cancers.As a result of the low cell permeability and poo...Src homology containing protein tyrosine phosphatase 2(SHP2)represents a noteworthy target for various diseases,serving as a well-known oncogenic phosphatase in cancers.As a result of the low cell permeability and poor bioavailability,the traditional inhibitors targeting the protein tyrosine phosphate catalytic sites are generally suffered from unsatisfactory applied efficacy.Recently,a particularly large number of allosteric inhibitors with striking inhibitory potency on SHP2 have been identified.In particular,few clinical trials conducted have made significant progress on solid tumors by using SHP2 allosteric inhibitors.This review summarizes the development and structureeactivity relationship studies of the small-molecule SHP2 inhibitors for tumor therapies,with the purpose of assisting the future development of SHP2 inhibitors with improved selectivity,higher oral bioavailability and better physicochemical properties.展开更多
Osteoarthritis(OA),in which M1 macrophage polarization in the synovium exacerbates disease progression,is a major cause of cartilage degeneration and functional disabilities.Therapeutic strategies of OA designed to in...Osteoarthritis(OA),in which M1 macrophage polarization in the synovium exacerbates disease progression,is a major cause of cartilage degeneration and functional disabilities.Therapeutic strategies of OA designed to interfere with the polarization of macrophages have rarely been reported.Here,we report that SHP099,as an allosteric inhibitor of src-homology 2-containing protein tyrosine phosphatase 2(SHP2),attenuated osteoarthritis progression by inhibiting M1 macrophage polarization.We demonstrated that M1 macrophage polarization was accompanied by the overexpression of SHP2 in the synovial tissues of OA patients and OA model mice.Compared to wild-type(WT)mice,myeloid lineage conditional Shp2 knockout(c KO)mice showed decreased M1 macrophage polarization and attenuated severity of synovitis,an elevated expression of cartilage phenotype protein collagen II(COL2),and a decreased expression of cartilage degradation markers collagen X(COL10)and matrix metalloproteinase3(MMP3)in OA cartilage.Further mechanistic analysis showed that SHP099 inhibited lipopolysaccharide(LPS)-induced Toll-like receptor(TLR)signaling mediated by nuclear factor kappa B(NF-κB)and PI3K—AKT signaling.Moreover,intra-articular injection of SHP099 also significantly attenuated OA progression,including joint synovitis and cartilage damage.These results indicated that allosteric inhibition of SHP2 might be a promising therapeutic strategy for the treatment of OA.展开更多
基金supported by National Natural Science Foundation of China(Nos.81673436,21472091,81872877,81673437)Mountain-Climbing Talents Project of Nanjing University,the Open Fund of State Key Laboratory of Pharmaceutical Biotechnology,Nanjing University(No.KF-GN-201703,China)+1 种基金Open Project Program of Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica(No.JKLPSE201802,China)the Project of the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD,China)
文摘Tyrosine phosphatase SHP2 is a promising drug target in cancer immunotherapy due to its bidirectional role in both tumor growth promotion and T-cell inactivation. Its allosteric inhibitor SHP099 is known to inhibit cancer cell growth both in vitro and in vivo. However, whether SHP099-mediated SHP2 inhibition retards tumor growth in vivo via anti-tumor immunity remains elusive. To address this, a CT-26 colon cancer xenograft model was established in mice since this cell line is insensitive to SHP099.Consequently, SHP099 minimally affected CT-26 tumor growth in immuno-deficient nude mice, but significantly decreased the tumor burden in CT-26 tumor-bearing mice with intact immune system.SHP099 augmented anti-tumor immunity, as shown by the elevated proportion of CD8tIFN-γtT cells and the upregulation of cytotoxic T-cell related genes including Granzyme B andPerforin, which decreased the tumor load. In addition, tumor growth in mice with SHP2-deficient T-cells was markedly slowed down because of enhanced anti-tumor responses. Finally, the combination of SHP099 and antiPD-1 antibody showed a higher therapeutic efficacy than either monotherapy in controlling tumor growthin two colon cancer xenograft models, indicating that these agents complement each other. Our study suggests that SHP2 inhibitor SHP099 is a promising candidate drug for cancer immunotherapy.
基金Our studies presented in this review article were supported by Grants-in-Aid for Scientific Research“S”(#16H06373 to M.H.),“A”(#22240085 and#25250016 to M.H.)and“C”(#19K05945 to A.T.-K.)Grants-in-Aid for Innovative Areas(#3205,#22114001,and#22114002 to M.H.)+4 种基金Grants-in-Aid for Japan Society for the Promotion of Science(JSPS)Fellows(#07J03878 to A.T.-K.and#19J12668 to C.T.K.)Grants-in-Aid for Young Scientists“B”(#24700965 and#15K18399 to A.T.-K.)the Graduate Program for Leaders in Life Innovation(GPLLI,to C.T.K.)from the Ministry of Education,Culture,Sports,Science and Technology(MEXT)of Japan,by CREST(#120200000396 to M.H.)Japan Science and Technology Agency,by the Uehara Memorial Foundation(#137 in 2016 to A.T.-K.)by the Max-Planck Society,Germany。
文摘Chronic infection with Helicobacter pylori cagA-positive strains is the strongest risk factor for gastric cancer.The cagA gene product,CagA,is delivered into gastric epithelial cells via the bacterial type IV secretion system.Delivered CagA then undergoes tyrosine phosphorylation at the Glu-Pro-Ile-Tyr-Ala(EPIYA)motifs in its C-terminal region and acts as an oncogenic scaffold protein that physically interacts with multiple host signaling proteins in both tyrosine phosphorylation-dependent and-independent manners.Analysis of CagA using in vitro cultured gastric epithelial cells has indicated that the nonphysiological scaffolding actions of CagA cell-autonomously promote the malignant transformation of the cells by endowing the cells with multiple phenotypic cancer hallmarks:sustained proliferation,evasion of growth suppressors,invasiveness,resistance to cell death,and genomic instability.Transgenic expression of CagA in mice leads to in vivo oncogenic action of CagA without any overt inflammation.The in vivo oncogenic activity of CagA is further potentiated in the presence of chronic inflammation.Since Helicobacter pylori infection triggers a proinflammatory response in host cells,a feedforward stimulation loop that augments the oncogenic actions of CagA and inflammation is created in CagA-injected gastric mucosa.Given that Helicobacter pylori is no longer colonized in established gastric cancer lesions,the multistep nature of gastric cancer development should include a“hit-and-run”process of CagA action.Thus,acquisition of genetic and epigenetic alterations that compensate for CagA-directed cancer hallmarks may be required for completion of the“hit-and-run”process of gastric carcinogenesis.
基金This work was supported by grants from the National Natural S&ence Foundation of China(grant Nos.81372844,81472474,81772804 and 81903092)Tianjin Municipal Science and Technology Commission(grant No.16JCYBJC25400)+1 种基金Changjiang Researchers and Innovative Research Team(grant No.IRT_14R40)Postgraduate Innovation Fund of"13th Five-Year Comprehensive Investment,"Tianjin Medical University(grant No.YJSCX201716).
文摘Objective:The tyrosine phosphatase SHP2 has a dual role in cancer initiation and progression in a tissue type-dependent manner.Several studies have linked SHP2 to the aggressive behavior of breast cancer cells and poorer outcomes in people with cancer.Nevertheless,the mechanistic details of how SHP2 promotes breast cancer progression remain largely undefined.Methods:The relationship between SHP2 expression and the prognosis of patients with breast cancer was investigated by using the TCGA and GEO databases.The expression of SHP2 in breast cancer tissues was analyzed by immunohistochemistry.CRISPR/Cas9 technology was used to generate SHP2-knockout breast cancer cells.Cell-counting kit-8,colony formation,cell cycle,and EdU incorporation assays,as well as a tumor xenograft model were used to examine the function of SHP2 in breast cancer proliferation.Quantitative RT-PCR,western blotting,immunofluorescence staining,and ubiquitination assays were used to explore the molecular mechanism through which SHP2 regulates breast cancer proliferation.Results:High SHP2 expression is correlated with poor prognosis in patients with breast cancer.SHP2 is required for the proliferation of breast cancer cellsin vitro and tumor growthin vivo through regulation of Cyclin D1 abundance,thereby accelerating cell cycle progression.Notably,SHP2 modulates the ubiquitin–proteasome-dependent degradation of Cyclin D1viathe PI3K/AKT/GSK3βsignaling pathway.SHP2 knockout attenuates the activation of PI3K/AKT signaling and causes the dephosphorylation and resultant activation of GSK3β.GSK3βthen mediates phosphorylation of Cyclin D1 at threonine 286,thereby promoting the translocation of Cyclin D1 from the nucleus to the cytoplasm and facilitating Cyclin D1 degradation through the ubiquitin–proteasome system.Conclusions:Our study uncovered the mechanism through which SHP2 regulates breast cancer proliferation.SHP2 may therefore potentially serve as a therapeutic target for breast cancer.
基金financial support by Guangdong Natural Science Funds for Distinguished Young Scholar(No.2018B030306017,China)Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme(2018)+4 种基金National Natural Science Foundation of China(Nos.81602972,81673436 and 91853109,China)The Fundamental Research Funds for the Central Universities(20ykzd15,China)Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery(2019B030301005,China)Guangzhou Science and Technology Project(202002020082,China)Key-Area Research and Development Program of Guangdong Province(2020B1111110003,China)
文摘Src homology containing protein tyrosine phosphatase 2(SHP2)represents a noteworthy target for various diseases,serving as a well-known oncogenic phosphatase in cancers.As a result of the low cell permeability and poor bioavailability,the traditional inhibitors targeting the protein tyrosine phosphate catalytic sites are generally suffered from unsatisfactory applied efficacy.Recently,a particularly large number of allosteric inhibitors with striking inhibitory potency on SHP2 have been identified.In particular,few clinical trials conducted have made significant progress on solid tumors by using SHP2 allosteric inhibitors.This review summarizes the development and structureeactivity relationship studies of the small-molecule SHP2 inhibitors for tumor therapies,with the purpose of assisting the future development of SHP2 inhibitors with improved selectivity,higher oral bioavailability and better physicochemical properties.
文摘SHP2 (Src homology 2 domain-containing protein tyrosine phosphatase-2)是由Ptpn11基因编码的非受体型蛋白酪氨酸磷酸酶,通过RAS (rat sarcoma)-ERK (extracellular regulated protein kinases)信号通路的活化调控细胞生长、分化和凋亡,并参与PD-1 (programmed cell death protein 1)/PD-L1(programmed cell death ligand 1)通路的免疫监控,已成为有突破意义的抗癌药物新靶标.靶向SHP2变构位点的抑制剂通过稳定SHP2非活性构象而抑制磷酸酶催化功能,具有很好的成药性.但是,SHP2功能获得性突变(gainoffunction,简称GOF)导致一系列发育障碍疾病和肿瘤的发生,并对SHP2野生型变构抑制剂产生耐药性.本工作首次以靶向SHP2激活突变体的变构抑制剂为靶头,基于PROTACs(proteolysis-targeting chimeras)技术,设计合成了一系列全新SHP2小分子降解剂.其中先导化合物3f和4d保持了对突变型SHP2^(E76A)的酶抑制活性,而且对于野生型SHP2依赖的人食管鳞癌细胞KYSE-520和突变型SHP2^(N58S)人大细胞肺癌细胞NCI-H661都显示强效抗增殖活性,比相应变构抑制剂的活性提高了5~10倍,为治疗SHP2突变或活化导致的遗传性疾病或肿瘤提供了新的干预策略.
基金supported by the National Science Foundation of China(NSFC 81802196,81572129,81872877,91853109,and 81772335)Key Program of NSFC(81730067,China)+3 种基金Special Program of Chinese Academy of Science(XDA16020805,China)Jiangsu Provincial Key Medical Center Foundation(China)Jiangsu Provincial Medical Outstanding Talent Foundation(China)Jiangsu Provincial Key Medical Talent Foundation(China)。
文摘Osteoarthritis(OA),in which M1 macrophage polarization in the synovium exacerbates disease progression,is a major cause of cartilage degeneration and functional disabilities.Therapeutic strategies of OA designed to interfere with the polarization of macrophages have rarely been reported.Here,we report that SHP099,as an allosteric inhibitor of src-homology 2-containing protein tyrosine phosphatase 2(SHP2),attenuated osteoarthritis progression by inhibiting M1 macrophage polarization.We demonstrated that M1 macrophage polarization was accompanied by the overexpression of SHP2 in the synovial tissues of OA patients and OA model mice.Compared to wild-type(WT)mice,myeloid lineage conditional Shp2 knockout(c KO)mice showed decreased M1 macrophage polarization and attenuated severity of synovitis,an elevated expression of cartilage phenotype protein collagen II(COL2),and a decreased expression of cartilage degradation markers collagen X(COL10)and matrix metalloproteinase3(MMP3)in OA cartilage.Further mechanistic analysis showed that SHP099 inhibited lipopolysaccharide(LPS)-induced Toll-like receptor(TLR)signaling mediated by nuclear factor kappa B(NF-κB)and PI3K—AKT signaling.Moreover,intra-articular injection of SHP099 also significantly attenuated OA progression,including joint synovitis and cartilage damage.These results indicated that allosteric inhibition of SHP2 might be a promising therapeutic strategy for the treatment of OA.
