SHP2靶向治疗在抗肿瘤研究中的进展

免疫治疗和靶向治疗是目前抗肿瘤精准治疗的主要方式,但耐药性的出现导致一些肿瘤患者无法从临床治疗中获益。含Src同源2结构域的蛋白酪氨酸磷酸酶2（Src homology 2 domain-containing protein tyrosine phosphatase 2,SHP2）参与细胞内多种级联信号通路。基于底物特异性的SHP2在不同组织类型的背景下,发挥着促癌或者抑癌的重要作用。近几年随着多种新开发的SHP2变构抑制剂的出现,SHP2已成为一些肿瘤的潜在药物靶点。对一些临床前癌症模型的研究表明,SHP2变构抑制剂与其他靶向药和/或免疫检查点阻断剂联合使用是精准治疗耐药癌症的一种很有前景的策略。本文主要综述了近年来SHP2在肿瘤和免疫细胞中的作用机制、在临床前模型中的肿瘤靶向和免疫治疗研究以及SHP2抑制剂在临床试验中的研究进展。     

酪氨酸磷酸酶PRL-3与肿瘤转移

肿瘤转移是恶性肿瘤最具破坏性的特征,也是癌症患者的主要死因之一。经过研究者们多年的努力,对肿瘤转移的过程有了较为清晰的了解,开始以一些关键分子,如血管内皮生长因子(vascular endothelial growth factor,VEGF)等作为治疗的靶点,但是,目前对肿瘤转移及肿瘤复杂本质的认识还不足于取得治疗上的突破。因而,更为深入地研究肿瘤转移的分子机理并鉴定转移特异标志物一直是肿瘤研究中的热点和重点。Saha等利用SAGE     

SHP2在吸烟肺癌患者肿瘤组织中的表达及意义

背景与目的蛋白质的磷酸化和去磷酸化是肺癌发生的重要机制,而吸烟是导致肺癌发生发展的重要危险因素,本研究旨在探讨蛋白酪氨酸磷酸酶SHP2在非小细胞肺癌(non-small cell Lung cancer,NSCLC)和小细胞肺癌(small cell lung cancer,SCLC)肿瘤组织中的表达及其临床意义,并初步探讨不同的吸烟指数与SHP2表达水平的关系及可能机制.方法采用免疫组织化学技术(Invision法)和荧光原位杂交技术(FISH法)检测53例肺癌组织中SHP2的表达和SHP2 mRNA的扩增情况.结果 SHP2在15例正常支气管上皮内弱阳性率为8096(亦为总阳性率);在48例NSCLC中弱阳性率为35.4%,中度阳性率为43.8%,强阳性率为6.2%(总阳性率为85.4%);在5例SCLC中弱阳性率为0%,中度阳性率为80%,强阳性率为20%(总阳性率为100%).SHP2在27例非吸烟NSCLC患者肿瘤组织中的弱阳性率为40.7%,中度阳性率为37.4%,强阳性率为3.7%(总阳性率为81.5%);SHP2在吸烟指数≥400的21例NSCLC患者肿瘤组织中弱阳性率为23.8%,中度阳性率为71.4%,强阳性率为4.7%(总阳性率为100%).等级计数资料秩和检验结果表明,肺癌组织中SHP2表达的阳性率显著高于正常支气管上皮(P<0.05),SCLC中SHP2的阳性率高于NSCLC(P<0.05),吸烟指数≥400的NSCLC癌组织中SHP2阳性率高于非吸烟患者(P<0.05).结论吸烟NSCLC患者肿瘤组织中SHP2的高表达可能与吸烟相关;SHP2可能在肺癌发生发展中起一定的作用;SHP2可能为肺癌治疗的药物研发提供新思路.     

酪氨酸激酶小分子抑制剂在肿瘤治疗中的研究

酪氨酸激酶的过度激活与肿瘤发生、发展、预后、转归密切相关.酪氨酸激酶激活可导致下游信号途径Ras-MAPK和PI3K-AKT的激活,最终抑制细胞凋亡,促进细胞生存.不同的酪氨酸激酶特异性抑制剂对不同的肿瘤具有特异性抑制作用.现综述此领域研究进展.     

蛋白酪氨酸磷酸酶1B与血液系统肿瘤关系研究进展

酪氨酸磷酸化是一种重要的调节细胞进程和维持稳态的翻译后修饰,酪氨酸磷酸化的异常改变常与疾病发生如代谢障碍、肿瘤和心血管疾病等密切相关.蛋白酪氨酸磷酸酶(PTP)是在细胞增殖和信号转导过程中调节蛋白酪氨酸残基磷酸化水平的酶家族.目前研究发现人类共有1 12种PTP,其中蛋白酪氨酸磷酸酶1B(PTP1B)是该家族中研究最热、最清楚的成员之一.近年来,PTP1B作为一种积极参与肿瘤发生的酶,引起了广泛关注.现就PTP1B与血液系统肿瘤关系的研究进展进行综述.     

SHP2作为抗肿瘤治疗靶点的价值及其在肿瘤免疫治疗中的应用

包含Src同源2结构域的蛋白酪氨酸磷酸酶2(Src homology region 2-containing protein tyrosine phosphatase 2,SHP2)是目前唯一被证实具有促癌作用的细胞质蛋白酪氨酸磷酸酶,在多种恶性肿瘤中高表达。SHP2可以通过介导受体酪氨酸激酶(Receptor tyrosine kinase,RTK)下游的RAS/ERK、PI3K/Akt和JAK/STAT等信号通路促进肿瘤发生发展,影响肿瘤预后。同时,SHP2参与调控PD-1/PD-L1、CTLA-4、BLTA和TIGIT等免疫检查点信号通路,对于肿瘤微环境中各种免疫细胞都有重要的调节作用。靶向SHP2不仅可以通过抑制RTK下游信号通路,还可以通过改善免疫微环境治疗恶性肿瘤。因此,SHP2具有免疫与靶向双重治疗肿瘤的功能,作为抗肿瘤治疗的靶点展现出极高的潜能与价值。     

肿瘤血管靶向治疗

根据作用机制及对血管抑制阶段的不同,肿瘤血管靶向治疗分为抗血管新生制剂和肿瘤血管阻断制剂.抗血管新生制剂旨在抑制肿瘤血管的新生,而肿瘤血管阻断制剂则通过快速而有选择性地损坏或阻塞已构建完成的肿瘤血管,使肿瘤血供受阻而引起肿瘤坏死.两者的区别主要体现在作用靶点、肿瘤类型及治疗时机上.     

酪氨酸激酶小分子抑制剂在肿瘤治疗中的研究

酪氨酸激酶的过度激活与肿瘤发生、发展、预后、转归密切相关。酪氨酸激酶激活可导致下游信号途径Ras-MAPK和P13K-AKT的激活，最终抑制细胞凋亡，促进细胞生存。不同的酪氨酸激酶特异性抑制剂对不同的肿瘤具有特异性抑制作用。现综述此领域研究进展。     

接头蛋白Gab1和酪氨酸磷酸酶SHP2在50例甲状腺乳头状癌中的表达及临床意义分析

[目的]探讨接头蛋白Gab1和酪氨酸磷酸酶SHP2在甲状腺乳头状癌中的表达及临床意义。[方法]收集2020年4月至2021年3月青岛大学附属医院收治的50例甲状腺乳头状癌患者的癌组织和癌旁组织。统计所有患者的年龄、性别、肿瘤大小、淋巴结转移情况、肿瘤分期(TNM分期)等临床资料。应用RT-qPCR、Western blot检测20例患者的新鲜组织标本,采用免疫组化方法检测50例患者的组织石蜡切片,探讨Gab1和SHP2的表达情况和临床意义。[结果](1)RT-qPCR和Western blot显示,Gab1和SHP2在甲状腺乳头状癌组织中的表达高于癌旁组织,差异具有统计学意义(P<0.05)。(2)免疫组化结果显示,Gab1和SHP2在癌组织中的表达(68.0%、64.0%)高于癌旁组织(36.0%、40.0%),差异有统计学意义(P<0.05)。(3)甲状腺乳头状癌组织中Gab1和SHP2的表达与肿瘤分期、淋巴结转移和肿瘤大小有关(P<0.05),在有淋巴结转移、较晚的分期和较大的肿瘤直径组中表达较高。(4)Gab1和SHP2高表达与患者年龄、性别无关。(5)Spearman相关性分析显示,Gab1和SHP2在甲状腺乳头状癌中的表达呈显著正相关(r=0.468,P=0.001)。[结论]Gab1和SHP2在甲状腺乳头状癌的发生中起着促癌基因的作用,与甲状腺乳头状癌的发展、转移及恶性程度有关。Gab1和SHP2在甲状腺乳头状癌发生、发展中存在协同作用的关系。     

骨髓增殖性肿瘤患者蛋白酪氨酸磷酸酶1B基因突变分析

目的 分析骨髓增殖性肿瘤(MPN)患者中蛋白酪氨酸磷酸酶1B(PTP1B)基因突变情况.方法 采用DNA测序技术检测84例MPN患者及37例健康对照者PTP1B的DNA序列.结果 MPN患者及健康对照者均未检测到Exon1 ～6、Exon9和Exon10突变.MPN患者中有18例检测到Exon8 C/T杂合性突变,健康对照者中有10例检测到C/T杂合性突变,两组之间差异无统计学意义(x 2=0.453,P=0.501).38例患者进行了Exon7基因测序,2例有C/T杂合性突变,健康对照者中有1例G/C杂合性突变.所有受试者均未检测到纯合性突变.结论 MPN患者PTP1B基因突变与健康对照者相比没有明显差异.     

Protein tyrosine phosphatase SHP2 promotes invadopodia formation through suppression of Rho signaling

Invadopodia are actin-enriched membrane protrusions that are important for extracellular matrix degradation and invasive cell motility. Src homolog domain-containing phosphatase 2 (SHP2), a non-receptor protein tyrosine phosphatase, has been shown to play an important role in promoting cancer metastasis, but the underlying mechanism is unclear. In this study, we found that depletion of SHP2 by short-hairpin RNA suppressed invadopodia formation in several cancer cell lines, particularly in the SAS head and neck squamous cell line. In contrast, overexpression of SHP2 promoted invadopodia formation in the CAL27 head and neck squamous cell line, which expresses low levels of endogenous SHP2. The depletion of SHP2 in SAS cells significantly decreased their invasive motility. The suppression of invadopodia formation by SHP2 depletion was restored by the Clostridium botulinum C3 exoenzyme (a Rho GTPase inhibitor) or Y27632 (a specific inhibitor for Rho-associated kinase). Together, our results suggest that SHP2 may promote invadopodia formation through inhibition of Rho signaling in cancer cells.     

Gene silencing of the tyrosine phosphatase SHP1 gene by aberrant methylation in leukemias/lymphomas

High-frequent silencing of hematopoietic cell-specific protein-tyrosine phosphatase SHP1 gene by promoter methylation was detected in various kinds of leukemias and lymphomas, as well as in many hematopoietic cell lines, which is supported by our previous observation of strong decrease of SHP1 mRNA and protein. The promoter methylation of the SHP1 gene was clearly correlated with the clinical stage. Loss of heterozygosity with microsatellite markers near the SHP1 gene was shown in 79% of informative acute lymphoblastic leukemia cases. These results suggest that functional loss of SHP1 is associated with the pathogenesis of leukemias/lymphomas.     

Epigenetic regulation and anti-tumorigenic effects of SH2-containing protein tyrosine phosphatase 1 (SHP1) in human gastric cancer cells

Tumor Biology - SH2-containing protein tyrosine phosphatase 1 (SHP1) is an important negative regulator in cytokine-mediated signal transduction and cell cycling. Recent studies have demonstrated...     

蛋白酪氨酸磷酸酶Shp2与肿瘤

Shp2（SH2 domain-containing protein-tyrosine phosphatase-2）分子由 PTPN11 基因编码,是一个在体内广泛存在的非受体型蛋白酪氨酸磷酸酶,既可以通过磷酸酶的催化活性来正向调控下游信号转导通路,也可以作为磷酸酶非依赖性的接头蛋白发挥正向调控作用,在特定的条件下亦可发挥负向调控作用,从而广泛参与细胞的分化、迁移等生物学功能的调控及相关的信号转导过程。 PTPN11 突变被认为是青少年粒单细胞白血病（juvenile myelomonocytic leukemia,JMML）的高危因素,同时,因其在不同类型白血病中均存在着 Shp2 的异常活化和突变而被认为是白血病的原癌基因;在前列腺癌、乳腺癌、胰腺癌、胃癌和神经胶质瘤中,Shp2也被报道呈过度活化状态;在肺癌中 Shp2 作为癌基因通过调控多种机制促进肿瘤的发生、发展。但在肝癌发生过程中, Shp2 却在特定环境的影响下发挥抑癌基因的作用。总之,作为重要的节点分子,Shp2在肿瘤发生、发展的过程中发挥着重要的调控作用,是潜在的治疗靶点。     

Targeting SHP2 sensitizes differentiated thyroid carcinoma to the MEK inhibitor

Pharmacologic targeting of components of the MAPK/ERK pathway in differentiated thyroid carcinoma (DTC) is often limited due to the development of adaptive resistance. However, the detailed mechanism of MEK inhibitor (MEKi) resistance is not fully understood. Here, MEKi-resistant models were constructed successfully, in which multiple receptor tyrosine kinases (RTKs) signaling pathways and Src-homology 2 domain-containing phosphatase 2 (SHP2) were activated in MEKi-resistant cells. Given the physiological role of SHP2 as the downstream target of many RTKs, we first found blockade of SHP2 enhanced the sensitivity to MEKi in constructed MEKi-resistant models. Interestingly, we also found that compared with MEKi treatment alone, MEKi in combination with an SHP2 inhibitor markedly suppressed the reactivation of the MEK/ERK pathway; thus, the addition of the SHP2 inhibitor significantly improved the antitumor effects of MEKi. The synergistic suppression of DTC upon treatment with both inhibitors was further confirmed in xenograft models and transgenic models. Thus, our data suggest that RTKs activation leads to reactivation of the MAPK pathway and resistance to MEKi in DTC, which is reversed by SHP2 blockade. As a novel active inhibitor of SHP2, SHP099 in combination with MEKi is a promising therapeutic approach for advanced DTC and MEKi-resistant one.     

The Shp-2 tyrosine phosphatase activates the Src tyrosine kinase by a non-enzymatic mechanism

Previously, we demonstrated that the Src tyrosine kinase interacts with the Shp-2 tyrosine phosphatase. To determine whether Shp-2 regulates Src kinase activity, we measured Src activity in cells overexpressing wild-type or catalytically-inactive C463S Shp-2. We observed a 2-3-fold increase in the specific activity of Src in both cell types and the increase did not appear to be due to dephosphorylation of Tyr 527 or phosphorylation of Tyr 416 on Src. Conversely, we observed a 2-3-fold decrease in the specific activity of Src when Shp-2 expression was inhibited. Using glutathione S-transferase-fusion proteins, we demonstrated that Shp-2 binds to the SH3 domain of Src. Our findings reveal that the Shp-2 tyrosine phosphatase can regulate the Src tyrosine kinase by a non-enzymatic mechanism. We also found that the phosphatase activity of Shp-2 immunoprecipitates is downregulated in cells transformed by Src or other proteins, and that Shp-2 preferentially associates with the membrane fraction of transformed cells. We suggest that membrane-association of Shp-2 is important for regulating Shp-2 activity.     

Therapeutic potential of directed tyrosine kinase inhibitor therapy in sarcomas.

BACKGROUND: Sarcomas are rare mesenchymally derived tumors for which there are limited treatment options. This paper discusses the current therapeutic potential of directed tyrosine kinase inhibitors (TKIs) in sarcoma. METHODS: The authors review antibody-based strategies and small molecular inhibitors of TKIs, with specific emphasis placed on the potential use of these targeted agents as therapeutic options for the treatment of sarcomas that are not gastrointestinal stromal tumors. RESULTS: Many TKs have been shown to be mutated or overexpressed in human sarcoma tumors and cell lines and may serve as potential targets for promising new sarcoma therapies. Furthermore, the novel mechanism of targeting TKs may complement the antitumor activity of existing sarcoma treatment options. CONCLUSIONS: TKIs such as imatinib, sunitinib, and sorefanib are promising new therapeutic options for the management of patients with soft tissue sarcoma.     

Predicting the response of CML patients to tyrosine kinase inhibitor therapy

Tyrosine kinase inhibitor (TKI) therapy has significantly changed the treatment paradigm for patients with chronic myeloid leukemia (CML). The firs-tgeneration inhibitor, imatinib, has demonstrated remarkable efficacy in most chronic-phase patients. Disease progression remains a significant risk for the first 2 to 3 years of TKI therapy, but the risk falls significantly thereafter. Early recognition of each individual’s risk of progression may facilitate a customized approach to TKI therapy. Using such an approach, drug selection and treatment intensity would be adjusted on the basis of each patient’s disease profile. Currently available prognostic indicators have limited value in the setting of the potent kinase inhibition afforded by TKIs. Furthermore, these indicators provide little guidance regarding optimal drug choice and dose intensity. In the future, assays that directly assess the efficacy of the protein—drug interaction, taking into account factors intrinsic to the patient and the amount of drug freely available in the plasma, are likely to be of greater value.     

A decade of tyrosine kinase inhibitor therapy: Historical and current perspectives on targeted therapy for GIST

The introduction of molecularly targeted therapies has ushered in a considerable transformation in the management of gastrointestinal stromal tumors (GIST) that currently defines the paradigm of targeted therapy for solid tumors. Indeed, in the past decade the management of GIST has evolved from a disease only effectively treatable by surgery to the archetype of a tumor treatable with a molecularly targeted therapy. Better understanding of the molecular and genetic characteristics that underlie the aberrant behavior of GIST has increased the accuracy of its diagnosis and allowed for the identification of distinct genetic hallmarks, prognostic groups, and treatment strategies. Collectively, this has resulted in the development of the targeted tyrosine kinase inhibitors (TKIs) imatinib and sunitinib, and continues to prompt studies of novel agents in this disease. Since approval in 2002, imatinib has been shown to provide a high level of clinical efficacy in patients with advanced GIST, including a median progression-free survival (PFS) of 2 years and median overall survival approaching 5 years, with some patients progression-free after 10 years of treatment. Imatinib is now also approved in adult patients following resection of KIT-positive GIST. In 2006, sunitinib was approved for the treatment of advanced GIST after failure of imatinib. Sunitinib provides significant benefit in this setting, with a median PFS close to 6 months after imatinib failure. Following progression on these agents, patients have limited treatment options. This critical unmet need is being addressed by the development of new TKIs and the use of novel regimens with approved agents.