TKI类药物在胃肠间质瘤临床应用中耐药机制的最新研究进展

胃肠间质瘤（gastrointestinal stromal tumor,GIST）是胃肠道最常见的间叶源性肿瘤.绝大多数GIST的发病机制是受c-KIT(KIT proto-oncogene receptor tyrosine kinase)或血小板衍生生长因子受体α(platelet-derived growth factor receptor alpha,PDGFRA)基因的功能增益性突变驱动。原先GIST的临床治疗方案仅为手术切除,而以伊马替尼（imatinib）为代表的小分子酪氨酸激酶抑制剂（tyrosine kinase inhibtor,TKI）的问世则标志着GIST治疗进入靶向治疗的时代。TKI在GIST中取得了显著的临床疗效,目前已有多个TKI药物被批准用于临床治疗,极大地提高了GIST患者的生存期,但是紧随而来的耐药问题是一个亟需解决的难点。目前已明确GIST对TKI耐药的主要原因是c-KIT或PDGFRA不同外显子的继发突变。然而,即使是带有相同外显子突变的GIST患者,其对TKI的反应仍存在较大差异,暗示着可能存在与c-KIT和PDGFRA同时作用的其它机制。得...     

非受体酪氨酸激酶靶点在胃肠间质瘤治疗中的研究现状与进展

胃肠间质瘤（gastrointestinal stromal tumor,GIST）是最常见的间叶细胞来源的胃肠肿瘤。75%～80%和10%的GIST分别存在编码受体酪氨酸激酶的KIT或PDGFRA激活突变,还有约10%的GIST不存在KIT和PDGFRA突变,称之为野生型GIST。GIST的治疗主要是以KIT及PDGFRA为靶点的受体酪氨酸激酶抑制剂（tyrosine kinase inhibitor,TKI）靶向治疗。然而,耐药问题一直是TKI治疗的难点和热点。野生型GIST对TKI治疗不敏感。近些年来,越来越多的研究开始关注非酪氨酸激酶靶点在GIST治疗中的潜在价值。本文对GIST分子分型及靶向治疗进行综述,着重探讨非酪氨酸激酶靶点在GIST治疗中的研究现状与进展。     

胃肠道间质瘤分子靶向治疗的研究进展

[摘要] 胃肠道间质瘤(gastrointestinal stromal tumor, GIST)是最常见的腹部软组织恶性肿瘤,来源于卡哈尔（Cajal）间质细胞或共同的前体细胞,由突变的KIT基因或血小板源性生长因子受体α（PDGFRα）基因驱动,均表达Ⅲ型酪氨酸激酶受体。酪氨酸激酶受体抑制剂伊马替尼用于晚期GIST的治疗取得了卓越的疗效,使得GIST成为实体肿瘤靶向药物治疗最成功的范例之一。之后随着对GIST分子生物学研究的日益深入,在精准医疗时代背景下,GIST的分子靶向治疗从晚期一线、二线、三线治疗到术后辅助治疗、术前治疗均有了清晰的脉络,从而为GIST患者提供了显著的生存获益。本文从晚期GIST 到早期GIST 的术前、术后分子靶向治疗进行了系统而全面的梳理,并分析问题、提出解决对策及对未来的展望,旨在为GIST临床分子靶向药物治疗提供参考。     

非编码RNA在胃肠间质瘤中的研究进展

胃肠间质瘤(gastrointestinal stromal tumor,GIST)是消化道最常见的间叶源性肿瘤,发病原因主要是由于原癌基因受体酪氨酸激酶或血小板衍生生长因子受体基因活化突变。分子靶向治疗药物甲磺酸伊马替尼是抑制KIT、血小板衍生生长因子受体α多肽(platelet-derived growth factor receptor alpha,PDGFRA)基因酪氨酸激酶活性的药物,其能有效治疗进展期GIST。但是,越来越多的研究发现,甲磺酸伊马替尼在治疗GIST过程中存在原发性耐药和继发性耐药。随着近年来对非编码RNA的生理功能和作用机制的深入研究,使人们逐步认识到非编码RNA对基因表达的广泛调控作用,其在肿瘤发生、发展、侵袭、转移和耐药等过程中扮演着重要角色。研究非编码RNA有可能为探讨GIST发病及耐药机制提供新的思路和方向。     

伊马替尼治疗胃肠道间质瘤的继发性耐药机制

甲磺酸伊马替尼是一种高效的酪氨酸激酶抑制剂,在临床上用于进展期或手术不能切除胃肠道间质瘤(GIST)的患者.虽然取得了很好的疗效,但是容易产生耐药,耐药机制主要有原发性耐药和继发性耐药,其中继发性耐药成为近些年研究的焦点.通过对继发性耐药机制的研究,可探讨新的治疗策略.     

伊马替尼治疗胃肠道间质瘤的继发性耐药机制

甲磺酸伊马替尼是一种高效的酪氨酸激酶抑制剂,在临床上用于进展期或手术不能切除胃肠道间质瘤(GIST)的患者.虽然取得了很好的疗效,但是容易产生耐药,耐药机制主要有原发性耐药和继发性耐药,其中继发性耐药成为近些年研究的焦点.通过对继发性耐药机制的研究,可探讨新的治疗策略.     

晚期胃肠间质瘤联合靶向药物治疗进展

胃肠间质瘤（gastrointestinal stromal tumors,GIST）是消化道最常见的间叶源性肿瘤,起源于Cajal间质细胞。所有的GIST均被认为具有一定程度的恶性潜能。KIT/血小板衍生生长因子受体α（platelet-derived growth factor receptor alpha,PDGFRA）基因突变导致的受体酪氨酸激酶编码蛋白异常激活,是目前已知GIST最主要的发病机制。酪氨酸酸激酶抑制剂（tyrosine kinase inhibitor,TKI）是治疗的主要选择,目前单药TKI序贯治疗是GIST的标准治疗方案,但一线治疗耐药以后,后线治疗的疗效有限。因此,针对不同靶点的药物联合治疗是目前重要的探索方向。在此,本文结合了近年来关于GIST联合靶向治疗的研究进展,包括两种TKI联合治疗、TKI与下游通路抑制剂联合治疗等,旨在对晚期GIST联合治疗的有效性及安全性进行全面的分析和讨论。     

非小细胞肺癌EGFR-TKIs耐药机制的研究进展

近年来,随着医学分子生物学的飞速发展,分子靶向治疗理念的提出使肿瘤治疗进入一个新阶段。在对非小细胞肺癌（NSCLC）的分子学研究中,表皮生长因子受体（EGFR）突变成为目前研究最热门的分子靶点,针对这一靶点的表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）如吉非替尼、厄洛替尼等,已经广泛应用于临床治疗。然而,有一部分患者对EGFR-TKIs的治疗并不敏感或对其产生耐药性,影响了EGFR-TKIs的临床疗效。本文就EGFR-TKIs的耐药机制以及解除耐药的相应策略进行综述。     

胃肠间质瘤的分子学研究进展

胃肠间质瘤(gastrointestinal stromal tumor,GIST)是最常见的消化道间质肿瘤.研究发现在绝大部分GIST中存在原癌基因KIT的获得性功能突变,KIT具有酪氨酸激酶受体活性,应用伊马替尼阻断KIT受体活性是治疗GIST的方法之一,这些研究结果改变了GIST的治疗方式和预后前景.GIST的分子学特征在疾病诊断、靶向药物剂量选择以及伊马替尼耐药中均起着重要作用.本文就GIST在分子学方面的研究进展作一综述.     

胃肠道间质瘤术后复发转移的治疗

  胃肠间质瘤（GIST）是消化道最常见的间叶组织来源的肿瘤。手术虽然是GIST的主要治疗方法，但不能治愈复发转移的GIST。如NCCN建议，复发转移的GIST应首选伊马替尼（STI571）。晚期和复发转移的GIST患者应该长期服用STI571，直到患者出现耐药而不能控制肿瘤。虽然复发转移再手术的效果很差，几乎100％会再复发转移，但病变能切除时或在能观察的病变在STI571治疗后一旦取得最大疗效反应时仍要外科手术或建议手术。关于STI571的新辅助和辅助治疗的试验正在研究中。另一种多靶点的酪氨酸激酶抑制剂SU11248正在临床试验中，对STI571无效或耐药的患者中约65 %获益。总之，合理的治疗方法和治疗时机对减少GIST复发转移、有效地控制疾病、提高生活质量以及生存率至关重要。     

Drug Insight: gastrointestinal stromal tumors (GIST)--the solid tumor model for cancer-specific treatment

We are living in an exciting era in the treatment of cancer, using drugs that target specific proteins rather than agents that cause more general cytotoxic effects. The identification of proteins and signal transduction pathways that play crucial roles in the pathogenesis of cancer has allowed treatments to be designed that target these tumor-driven events. Gastrointestinal stromal tumors (GIST) are rare mesenchymal tumors and were among the first solid tumor types for which such a novel treatment (in this case imatinib) became available. The tyrosine kinase inhibitor imatinib targets the human KIT receptor and the platelet-derived growth factor receptor-alpha. This drug exhibits impressive antitumor effects against GIST and has become the first-line therapy for advanced disease. Major insights into the mechanism of action of this drug, drug resistance, and patient management issues have been gleaned. Additionally, new drugs developed for the treatment of GIST have been identified. As a consequence, lessons learned from GIST are widely applicable to other tumor entities, thereby rendering GIST the paradigm of solid tumors treated with tyrosine kinase inhibitors. This Review discusses the pathogenesis of GIST, treatment strategies, mechanisms accounting for drug resistance, and potential future perspectives.     

Gastrointestinal stromal tumors: molecular aspects and therapeutic implications

Approximately 90 % of gastrointestinal tumors (GISTs) harbor an activating mutation in KIT or PDGFR alpha oncogene known to confer imatinib sensitivity. Imatinib is a tyrosine kinase inhibitor of KIT and PDGFRs that yields a 6-months progression-free survival (PFS) rate of 80 % in patients with advanced GISTs. Several studies have shown that response to imatinib in GIST patients mainly depends on the mutational status of KIT or PDGFR alpha. Moreover, most if not all patients treated with imatinib for advanced GIST will secondarily develop progressive disease under treatment. In the majority of cases, such progressions are the result of acquired resistance due to occurrence of secondary C-KIT mutations; especially for GIST with primary exon 11 mutations. Sunitinib is another approved drug and an inhibitor of multiple tyrosine kinases including KIT, PDGFR alpha as well as PDGFR beta and VEGFRs which are associated with angiogenesis. Sunitinib, in phase II and III trials was associated with durable clinical benefit in nearly 25 % of patients with advanced GIST resistant/intolerant to imatinib. Clearly, a better knowledge of the molecular mechanisms underlying the resistance to imatinib as well as the development of a new class of broad-spectrum tyrosine kinase inhibitors may allow in the near future new individualized therapeutic strategies for GISTs patients.     

Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation.

Most gastrointestinal stromal tumors (GIST) have an activating mutation in either KIT or PDGFRA. Imatinib is a selective tyrosine kinase inhibitor and achieves a partial response or stable disease in about 80% of patients with metastatic GIST. It is now clear that some patients with GIST develop resistance to imatinib during chronic therapy. To identify the mechanism of resistance, we studied 31 patients with GIST who were treated with imatinib and then underwent surgical resection. There were 13 patients who were nonresistant to imatinib, 3 with primary resistance, and 15 with acquired resistance after initial benefit from the drug. There were no secondary mutations in KIT or PDGFRA in the nonresistant or primary resistance groups. In contrast, secondary mutations were found in 7 of 15 (46%) patients with acquired resistance, each of whom had a primary mutation in KIT exon 11. Most secondary mutations were located in KIT exon 17. KIT phosphorylation was heterogeneous and did not correlate with clinical response to imatinib or mutation status. That acquired resistance to imatinib in GIST commonly occurs via secondary gene mutation in the KIT kinase domain has implications for strategies to delay or prevent imatinib resistance and to employ newer targeted therapies.     

Molecular basis for primary and secondary tyrosine kinase inhibitor resistance in gastrointestinal stromal tumor

Small molecule kinase inhibitors have irrevocably altered cancer treatment. March 2010 marks the 10th anniversary of using imatinib in gastrointestinal stromal tumors (GIST), a cardinal example of the utility of such targeted therapy in a solid tumor. Before imatinib, metastatic GIST was frustrating to treat due to its resistance to standard cytotoxic chemotherapy. Median survival for patients with metastatic GIST improved from 19 to 60?months with imatinib. In treating patients with GIST, two patterns of tyrosine kinase inhibitor resistance have been observed. In the first, ~9-14% of patients have progression within 3?months of starting imatinib. These patients are classified as having primary or early resistance. Median progression-free survival (PFS) on imatinib is approximately 24?months; patients with later progression are classified as having secondary or acquired resistance. Primary studies and a meta-analysis of studies of imatinib in GIST patients have identified prognostic features that contribute to treatment failure. One of the strongest predictors for success of therapy is KIT or PDGFRA mutational status. Patients with KIT exon 11 mutant GIST have better response rates, PFS, and overall survival compared to other mutations. A great deal has been learned in the last decade about sensitivity and resistance of GIST to imatinib; however, many unanswered questions remain about secondary resistance mechanisms and clinical management in the third- and fourth-line setting. This review will discuss the role of dose effects, and early and late resistance to imatinib and their clinical implications. Patients intolerant to imatinib (5%) and those who progress on imatinib are treated with sunitinib. The mechanism of resistance to sunitinib is unknown at this time but is also appears related to growth of clones with secondary mutations in KIT. Third- and fourth-line treatments of GIST and with future treatment strategies are also discussed.     

Differential properties of current tyrosine kinase inhibitors in gastrointestinal stromal tumors

During the past decade, tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of gastrointestinal stromal tumors (GIST), providing new treatment options with unprecedented clinical benefit. Recognition of the key role played by the receptor tyrosine kinases KIT and platelet-derived growth factor receptor alpha (PDGFRα) in the pathogenesis of GIST led to the development of imatinib, the first TKI for this indication and the current first-line standard of care for unresectable or metastatic GIST. However, the clinical efficacy of imatinib is limited by two concerns: the rare patient-specific intolerance to the drug, and the fact that the majority of patients will eventually develop treatment-refractory disease that is resistant to this selective TKI. Although sunitinib has been approved worldwide as second-line therapy for GIST following failure of imatinib, the benefits of sunitinib in treating GIST following imatinib failure are most often more limited than first-line therapy, with emergence of treatment-resistant disease in less than 1 year. Other TKIs studied in clinical trials for GIST include a wide range of different agents, such as sorafenib, dasatinib, pazopanib, regorafenib, masitinib, and nilotinib. Each agent differs in its selectivity for individual tyrosine kinases, conferring each with distinct properties that determine clinical safety and efficacy. No agent has yet reached regulatory approval for management of GIST following the failure of both imatinib and sunitinib. This review highlights relevant differences and similarities in the structures and functions, including kinase selectivity and mechanisms of binding, of the currently approved TKIs and certain others in development for the treatment of advanced GIST. In addition, the ability of some TKIs to inhibit alternative targets with potency similar to or greater than their intended primary target (pleiotropic effects) is also discussed.     

Improved insight into resistance mechanisms to imatinib in gastrointestinal stromal tumors: a basis for novel approaches and individualization of treatment

Gastrointestinal stromal tumor (GIST) is one of the first solid tumor types in which a tyrosine kinase inhibitor, imatinib, has become standard of care for patients with advanced disease. Although imatinib yields antitumor activity in the vast majority of patients, it is likely that all patients eventually experience progressive disease given enough time. In recent years, major progress has been made in the elucidation of mechanisms conferring resistance to imatinib that result in progressive disease. Insight into these resistance mechanisms has already resulted in the availability of strategies that can be applied in cases of progressive disease and it is likely that more approaches will be defined in the next years. Additionally, it can be anticipated that in the near future treatment will be guided according to factors determining sensitivity to imatinib. This review focuses on the factors inducing imatinib resistance that have been elucidated so far, the currently available and potential novel treatment options for patients with progressive disease, and how insight into resistance mechanisms may allow individualized treatment in the near future for patients with advanced GISTs.     

New findings of kinase switching in gastrointestinal stromal tumor under imatinib using phosphoproteomic analysis

Despite the revolutionary effects of imatinib on advanced gastrointestinal stromal tumors (GISTs), most patients eventually develop disease progression following primary resistance or acquired resistance driven by secondary‐resistant mutations. Even in radiographically vanishing lesions, pathology has revealed persistent viable cells during imatinib therapy, which could lead to the emergence of drug‐resistant clones. To uncover the mechanisms underlying these clinical issues, here we examined imatinib‐induced phosphoproteomic alterations in GIST‐T1 cells, using our quantitative tyrosine phosphoproteomic analysis method, which combined immunoaffinity enrichment of phosphotyrosine‐containing peptides with isobaric tags for relative and absolute quantitation (iTRAQ) technology. Using this approach, we identified 171 tyrosine phosphorylation sites spanning 134 proteins, with 11 proteins exhibiting greater than 1.5‐fold increases in tyrosine phosphorylation. Among them, we evaluated FYN and focal adhesion kinase (FAK), both of which are reportedly involved in proliferation and malignant alteration of tumors. We confirmed increased tyrosine phosphorylation of both kinases by western blotting. Inhibition of FYN and FAK phosphorylation each increased tumor cell sensitivity to imatinib. Furthermore, a FAK‐selective inhibitor (TAG372) induced apoptosis of imatinib‐resistant GIST‐T1 cells and decreased the imatinib IC₅₀. These results indicate that FYN or FAK might be potential therapeutic targets to overcome resistance to imatinib in GISTs. Additionally, we showed that the iTRAQ‐based quantitative phosphotyrosine‐focused phosphoproteomic approach is a powerful method for screening phosphoproteins associated with drug resistance.     

A long-term survival case with multiple liver metastases from duodenal gastrointestinal stromal tumor that was drastically reduced by the treatment with imatinib

Constitutive activation of c-kit receptor tyrosine kinase is a critical factor in the pathogenesis of gastrointestinal stromal tumors. Imatinib mesylate (IM), a selective tyrosine kinase inhibitor, has been shown in clinical studies to work against such tumors. But there is little information on whether a combination of IM and surgical treatment can prolong survival in a case of unresectable multiple liver metastases. We report a case of postoperative recurrence of gastrointestinal stromal tumor (GIST) treated by the tyrosine kinase inhibitor IM and surgical treatment. Therefore, we discuss some important implications. This 37-year-old Japanese man underwent a pancreaticoduodenectomy for GIST of the duodenum in January 2003. The postoperative course was good at first, but 3 months after the initial operation, MRI showed multiple liver metastases. The patient was treated with 400 mg of IM once daily with only weak liver dysfunction as a side effect. The initial response to treatment of CR continued for 18 months. Currently, IM is the first-line therapy for non-resectable GISTs. As the mechanisms of recurrence and resistance to imatinib in GIST remain unclear, they should be intensively performed in the sight of both clinical and molecular biological viewpoints. Further examination in more cases of recurrent GIST is also necessary to estimate the effectiveness of treatment with IM.     

Molecular analysis of secondary kinase mutations in imatinib-resistant gastrointestinal stromal tumors

Most gastrointestinal stromal tumors (GISTs) are associated with activating kinase mutation in KIT or platelet-derived growth factor receptor alpha (PDGFRA) gene, and imatinib has revolutionized the care of advanced GISTs. However, most patients gradually developed resistance to imatinib. We intend to identify the secondary kinase mutations in imatinib-resistant GISTs and to study the relationship between secondary kinase mutations and the clinical response to imatinib. Twelve advanced GIST patients, who have developed resistance to imatinib were included in this study. Paraffin-embedded pretreatment GIST specimens and progression lesions of the tumors after resistance to imatinib were analyzed for kinase mutations in exons 9, 11, 13, and 17 of KIT gene and exons of 10, 12, 14, and 18 of PDGFRA gene. Primary KIT mutations have been found in all but one of the primary tumors including one case harboring de novo double KIT exon 11 mutations. Secondary kinase mutations in KIT and PDGFRA were found in seven and 1 of 12 patients, respectively. Two patients harbored more than one secondary KIT mutations in different progression sites, and there are four types of clonal or polyclonal evolution being observed. The secondary PDGFRA exon 14 mutation H687Y is a novel mutation that has never been reported before. Acquired secondary kinase mutations are the most important cause of secondary imatinib resistance in advanced GISTs. The identification of secondary kinase mutations is important in the development of new therapeutic strategies.