非小细胞肺癌治疗中吉非替尼继发耐药的机制研究进展

吉非替尼(gefitinib)是表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor tyrosinekinase inhibitors,EGFR-TKIs)类靶向药物,目前主要用于治疗已接受过铂类为基础化疗的非小细胞肺癌进展期患者。然而,靶向药物同样存在着继发耐药的问题。关于继发耐药的相关研究中,目前普遍认同是表皮生长因子受体(epidermal growth factor receptor,EGFR)基因的二次突变学说;但亦有研究显示,吉非替尼的耐药与药物的转运、EGFR/Met基因的扩增以及信号通路的改变有关,非单一机制能完全解释其耐药性。因此,本文将对目前关于吉非替尼继发耐药的机制以及克服耐药的策略的研究进展作一综述。     

阿帕替尼逆转阿法替尼耐药治疗EGFR20外显子插入突变晚期非小细胞肺癌1例

恶性肿瘤严重威胁人们的生命健康,尤其是肺癌。随着对肺癌分子生物学的深入研究以及相关靶向药物的开发,靶向治疗已经改变了晚期肺癌的治疗格局。目前肺癌靶向治疗耐药机制成为研究的热点。本文报道1例阿帕替尼逆转经阿法替尼治疗耐药的表皮生长因子受体(epidermal growth factor receptor-tyrosine kinase,EGFR)20外显子插入突变晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)患者的治疗过程,并做文献复习。     

非小细胞肺癌中奥希替尼耐药机制及应对策略的研究进展

奥希替尼作为第三代表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI), 在携带EGFR突变的非小细胞肺癌(NSCLC)患者的靶向治疗中取得了显著的临床效益, 但其耐药不可避免。为了应对奥希替尼的药物抵抗, 新一代靶向药物的研发及相应的治疗策略也在发展中, 并有部分已进入临床试验。文章主要对奥希替尼的耐药机制及其耐药后治疗策略的研究进展进行综述。     

表皮生长因子受体小分子抑制剂埃罗替尼应用研究进展

表皮生长因子受体(EGFR)异常表达与肿瘤细胞的增殖、血管生成、肿瘤侵袭、转移及细胞凋亡的抑制有关.EGFR小分子抑制剂埃罗替尼(erlotinib)是一种表皮生长因子酪氨酸激酶可逆性抑制剂,通过抑制酪氨酸激酶的磷酸化,阻断信号转导,抑制肿瘤生长.埃罗替尼在治疗非小细胞肺癌中有良好作用,在神经胶质瘤及其他EGFR异常表达的肿瘤中尚未显示显著疗效.埃罗替尼和其他抗肿瘤药物联合应用越来越受到重视,埃罗替尼和其他靶向制剂或化疗药的联合治疗方案可能成为未来肿瘤治疗的一个重要策略.     

厄洛替尼治疗失败后埃克替尼靶向治疗晚期非小细胞肺癌1例报道

厄洛替尼和埃克替尼是一种选择性表皮生长因子受体（epidermal growth factor receptor,EGFR）——酪氨酸激酶抑制剂（tyrosine kinase inhibitor,TKI）,在进展期非小细胞肺癌（NSCLC）中具有靶向治疗作用。靶向药物治疗一般作为二线或三线用药,其治疗失败后很少有行之有效的治疗策略。本文报道1例晚期NSCLC厄洛替尼治疗失败后采用埃克替尼靶向治疗有效的病例。     

吉非替尼在非小细胞肺癌治疗中耐药机制的研究进展

吉非替尼(gefitinib)是表皮生长因子受体(epidermal growth factor receptor,EGFR)酪氨酸激酶抑制剂类靶向药物,与传统化疗药物相比,从细胞受体、增值调控的分子水平对肿瘤发病机制进行调控的靶向药物吉非替尼可使EGFR突变阳性患者的无疾病进展生存期显著延长。     

吉非替尼在非小细胞肺癌治疗中的继发耐药

吉非替尼是一种表皮生长因子受体(EGFR)酪氨酸激酶抑制剂,对非小细胞肺癌(NSCLC)有良好的抗肿瘤活性,但大多数患者最终因继发耐药出现病情进展.在发生EGFR基因突变的肺腺癌患者中,约半数吉非替尼继发耐药与二次突变有关,这种二次突变导致EGFR 790位上的苏氨酸被甲硫氨酸所取代(T790M).其他导致耐药的机制包括EGFR受体的内化现象以及MET基因扩增.     

埃罗替尼治疗吉非替尼耐药的晚期非小细胞肺癌有效1例

晚期非小细胞肺癌（NSCLC）预后差,以化疗为主的联合治疗只能降低死亡风险26％-32％。近年来,非小细胞肺癌的靶向治疗成为研究热点,其中尤以表皮生长因子受体酪氨酸激酶抑制剂（EGFR—TKI）进展最快,其代表药物吉非替尼（gefitinib、iressa）和埃罗替尼（erlotinib、tarceva）。我科用埃罗替尼治疗吉非替尼耐药的晚期非小细胞肺癌（NSCLC）一例取得了较好疗效,现报告如下。     

晚期非小细胞肺癌厄洛替尼耐药研究进展

酪氨酸激酶抑制剂(TKI)厄洛替尼作为晚期非小细胞肺癌(NSCLC)靶向治疗药物,延长了患者的生存时间,但其耐药性的发生成为其进一步应用的瓶颈.现已证实T790M突变、KRAS突变、c-met癌基因扩增在耐药机制中起重要作用.针对不同耐药机制,第2代TKI的应用、再次应用化疗或厄洛替尼以及针对失败模式进行后续治疗等多项临床试验不断开展.     

埃罗替尼治疗吉非替尼耐药的晚期非小细胞肺癌有效1例

晚期非小细胞肺癌(NSCLC)预后差,以化疗为主的联合治疗只能降低死亡风险26%-32%[1].近年来,非小细胞肺癌的靶向治疗成为研究热点,其中尤以表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)进展最快,其代表药物吉非替尼(gefitinib、iressa)和埃罗替尼(erlotinib、tarceva).我科用埃罗替尼治疗吉非替尼耐药的晚期非小细胞肺癌(NSCLC)一例取得了较好疗效,现报告如下.     

非小细胞肺癌分子靶向治疗及其耐药

以吉非替尼和厄洛替尼为代表的表皮生长因子受体酪氨酸激酶抑制剂在非小细胞肺癌治疗中发挥重要作用,然而在临床前和临床研究中发现,许多患者对此类药物存在原发性耐药或获得性耐药,使其临床应用受到一定限制.目前许多研究致力于延缓、逆转耐药以及开发新的靶点,为非小细胞肺癌的靶向治疗提供了更多的可能.     

Molecular markers in colorectal cancer: genetic bases for a customised treatment

Colorectal cancer (CRC) is the second leading cause of cancer death in Western countries. CRC treatment is based on the employment of three chemotherapeutic drugs, including 5-fluorouracil, oxaliplatin and irinotecan, and the use of recently incorporated targeted agents directed to vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR). The approval of these biologicals and of others to come holds great promise for the improvement of patient outcome. The molecular bases for this lethal disease have been extensively investigated, laying the foundations for a rational and customised treatment approach, expanding the therapeutic index of current drugs and easing the incorporation of new molecules. Individual markers have been mainly investigated based on drug targets and metabolism. Also, the increasing availability of highthroughput technologies has prompted the opportunity for blind studies capable of screening new markers and of identifying the specific oncogenic pathways responsible for drug resistance in a given patient. An updated review of the field is presented in this article.     

Targeting receptor tyrosine kinases and their signal transduction routes in head and neck cancer.

Squamous cell carcinoma of the head and neck (SCCHN) is the sixth most common cancer in the world. At present several therapeutic approaches, including surgical removal, chemotherapy and radiotherapy, are used. Yet a significant number of patients relapse, often with metastases. In an attempt to improve treatment of SCCHN new targeted therapies are emerging. Among them special interest has been devoted to agents that act on the epidermal growth factor receptor (EGFR) and other receptor tyrosine kinases, or the signal transduction routes used by these receptors to induce tumour cell proliferation. Such treatments include monoclonal antibodies and small molecule inhibitors of either the intracellular tyrosine kinase activity of these receptors or relevant signalling intermediates. Here we review the biological bases of these new targeted treatments, with special emphasis on the clinical results that point to an implementation of these drugs into the therapeutic armamentarium against SCCHN.     

Targeted therapies in the treatment of non-small cell lung cancer

New targeted treatments offer an important opening towards the improvement of the results in the treatment of lung cancer. Currently two types of therapeutic targets are developed successfully in the treatment of advanced non-small cell lung cancer: tumour angiogenesis and growth factor receptors. Therapeutic drugs are small molecules inhibitors and the monoclonal antibodies. Bevacizumab is a monoclonal antibody against vascular endothelial growth factor receptor, VEGF, an important molecule in tumour angiogenesis. The combination of bevacizumab with first line chemotherapy increases the median survival of advanced NSCLC with a few weeks. At this moment no biomarker predicting efficacy that can help in the selection of patients is unfortunately available for this expensive treatment, although it is important to select patients based on specific contra-indications. The epidermal growth factor receptor (EGFR or HER1) is activated in NSCLC by several mechanisms. The small molecules erlotinib and gefitinib are targeting the intracellular kinase domain of the EGF receptor, thus inhibiting the signal transduction cascade. Erlotinib is currently registered and reimbursed in Belgium. The concomitant use of these small molecules with chemotherapy is ineffective in non-selected NSCLC patients. On the other hand, these molecules have great activity in patients with tumours having a constitutionally activated EGFR. Changes in the kinase domain of the receptor give rise to extremely high response rates and unexpectedly improved survival duration in patients with NSCLC. Currently studies are exploring whether erlotinib should be employed in the first line treatment of NSCLC. The FIELT study is a translational academic and multicentre phase II study in Belgium and Luxemburg addressing this issue. Specific mechanisms of resistance for these agents are gradually discovered and the new drugs being able to overcome these resistances are at the horizon.     

Targeted therapy in advanced colorectal cancer, an update

The introduction of inhibitors of signal transduction pathways has increased the therapeutic arsenal for patients with advanced colorectal cancer (ACC). Bevacizumab, a monoclonal vascular endothelial growth factor antibody, is currently part of the standard first-line treatment in combination with fluoropyrimidine-based chemotherapy. Cetuximab, a chimeric monoclonal antibody against the epidermal growth factor receptor, has shown efficacy in irinotecan-refractory ACC patients. Several experimental targeted agents, including small molecules that inhibit receptor tyrosine kinase activity, are currently being tested. We review the mechanism of action as well as the current status of targeted therapy in ACC.     

Efficacy and mechanism of action of the tyrosine kinase inhibitors gefitinib,lapatinib and neratinib in the treatment of HER2-positive breast cancer: preclinical and clinical evidence

An increasing number of tumors, including breast cancer, overexpress proteins of the epidermal growth factor receptor (EGFR) family. The interaction between family members activates signaling pathways that promote tumor progression and resistance to treatment. Human epidermal growth factor receptor type II (HER2) positive breast cancer represents a clinical challenge for current therapy. It has motivated the development of novel and more effective therapeutic EGFR family target drugs, such as tyrosine kinase inhibitors (TKIs). This review focuses on the effects of three TKIs mostly studied in HER2- positive breast cancer, lapatinib, gefitinib and neratinib. Herein, we discuss the mechanism of action, therapeutic advantages and clinical applications of these TKIs. To date, TKIs seem to be promising therapeutic agents for the treatment of HER2-overexpressing breast tumors, either as monotherapy or combined with other pharmacological agents.     

Recent clinical developments and rationale for combining targeted agents in non-small cell lung cancer (NSCLC)

While chemotherapy has been the standard of care for patients with advanced non-small cell lung cancer (NSCLC), efforts have shifted toward evaluating novel targeted agents in an attempt to improve outcome. These targeted agents are directed toward key components in several signalling pathways such as vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), epidermal growth factor receptor (EGFR) and insulin-like growth factor 1 receptor (IGF-IR). There is also increasing interest in using combinations of targeted agents to inhibit more than one pathway; for example, inhibition of VEGFR + EGFR and VEGFR + PDGFR + EGFR. Further investigation is needed to identify the most appropriate combinations of these targeted agents in select patient subgroups, and to define optimal treatment doses to thereby achieve the best therapeutic index. This review outlines the rationale for combining targeted agents for the treatment of advanced NSCLC.     

The platelet-derived growth factor receptor as a therapeutic target

Several small molecule tyrosine kinase inhibitors that block the epidermal growth factor receptor and vascular endothelial growth factor receptor function are among the many recently developed targeted anticancer therapeutic agents. Increasing evidence indicates that inhibition of other tumor stromal targets could provide additional and possibly synergistic antitumor effects. This article focuses on the platelet-derived growth factor receptor as one such potential target.     

Mechanisms and therapeutic advances in the management of endocrine-resistant breast cancer

The estrogen receptor (ER) pathway plays a critical role in breast cancer development and progression. Endocrine therapy targeting estrogen action is the most important systemic therapy for ER positive breast cancer. However its efficacy is limited by intrinsic and acquired resistance. Mechanisms responsible for endocrine resistance include deregulation of the ER pathway itself, including loss of ER expression, post-translational modification of ER, deregulation of ER co-activators; increased receptor tyrosine kinase signaling leading to activation of various intracellular pathways involved in signal transduction, proliferation and cell survival, including growth factor receptor tyrosine kinases human epidermal growth factor receptor-2, epidermal growth factor receptor, PI3K/AKT/mammalian target of rapamycin (mTOR), Mitogen activated kinase (MAPK)/ERK, fibroblast growth factor receptor, insulin-like growth factor-1 receptor; alterations in cell cycle and apoptotic machinery; Epigenetic modification including dysregulation of DNA methylation, histone modification, and nucleosome remodeling; and altered expression of specific microRNAs. Functional genomics has helped us identify a catalog of genetic and epigenetic alterations that may be exploited as potential therapeutic targets and biomarkers of response. New treatment combinations targeting ER and such oncogenic signaling pathways which block the crosstalk between these pathways have been proven effective in preclinical models. Results of recent clinical studies suggest that subsets of patients benefit from the combination of inhibitor targeting certain oncogenic signaling pathway with endocrine therapy. Especially, inhibition of the mTOR signaling pathway, a key component implicated in mediating multiple signaling cascades, offers a promising approach to restore sensitivity to endocrine therapy in breast cancer. We systematically reviewed important publications cited in PubMed, recent abstracts from ASCO annual meetings and San Antonio Breast Cancer Symposium, and relevant trials registered at ClinicalTrials.gov. We present the molecular mechanisms contributing to endocrine resistance, in particular focusing on the biological rationale for the clinical development of novel targeted agents in endocrine resistant breast cancer. We summarize clinical trials utilizing novel strategies to overcome therapeutic resistance, highlighting the need to better identify the appropriate patients whose diseases are most likely to benefit from these specific strategies.     

头颈部鳞癌分子靶向治疗进展

当前分子靶向治疗头颈部鳞状细胞癌(SCCHN)的进展非常快.由于表皮生长因子受体(EGFR)信号传导和血管发生在SCCHN的生长中起关键作用,因此EGFR及其下游效应器与血管发生过程相关的分子及其受体就成为目前SCCHN分子靶向治疗的主要靶点.