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肺癌分子靶向药物耐药机制的研究进展
随着肺癌分子发病机制的阐明,针对这些分子机制的靶向治疗逐步进入临床,其中表皮生长因子受体(EGFR)是目前研究多、公认有效的肺癌治疗靶点.然而,EGFR酪氨酸激酶(TK)抑制剂(TKI)只对部分患者有效.因此了解肺癌耐受分子靶向药物的机制有助于指导临床用药,并为将来开发新的靶向治疗措施提供依据.现将EGFR-TKI的耐药机制综述如下.
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Receptor tyrosine kinases (RTKs) such as the epidermal growth factor receptor (EGFR) regulate cellular homeostatic processes. EGFR activates downstream signaling cascades that promote tumor cell survival, proliferation and migration. Dysregulation of EGFR signaling as a consequence of overexpression, amplification and mutation of the EGFR gene occurs frequently in several types of cancers and many become dependent on EGFR signaling to maintain their malignant phenotypes. Consequently, concerted efforts have been mounted to develop therapeutic agents and strategies to effectively inhibit EGFR. However, limited therapeutic beneifts to cancer patients have been derived from EGFR-targeted therapies. A well-documented obstacle to improved patient survival is the presence of EGFR-inhibitor resistant tumor cell variants within heterogeneous tumor cell masses. Here, we summarize the mechanisms by which tumors resist EGFR-targeted therapies and highlight the emerging role of microRNAs (miRs) as downstream effector molecules utilized by EGFR to promote tumor initiation, progression and that play a role in resistance to EGFR inhibitors. We also examine evidence supporting the utility of miRs as predictors of response to targeted therapies and novel therapeutic agents to circumvent EGFR-inhibitor resistance mechanisms.
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ABCC10, also known as multidrug-resistant protein 7 (MRP7), is the tenth member of the C subfamily of the ATP-binding cassette (ABC) superfamily. ABCC10 mediates multidrug resistance (MDR) in cancer cells by preventing the intracellular accumulation of certain antitumor drugs. The ABCC10 transporter is a 171-kDa protein that is localized on the basolateral cell membrane. ABCC10 is a broad-specificity transporter of xenobiotics, including antitumor drugs, such as taxanes, epothilone B, vinca alkaloids, and cytarabine, as wel as modulators of the estrogen pathway, such as tamoxifen. In recent years, ABCC10 inhibitors, including cepharanthine, lapatinib, erlotinib, nilotinib, imatinib, sildenafil, and vardenafil, have been reported to overcome ABCC10-mediated MDR. This review discusses some recent and clinically relevant aspects of the ABCC10 drug efflux transporter from the perspective of current chemotherapy, particularly its inhibition by tyrosine kinase inhibitors and phosphodiesterase type 5 inhibitors.
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酪氨酸激酶抑制剂耐药机制及其治疗策略
人类表皮生长因子受体(epiderma l growth factorreceptor, EGFR)是原癌基因C-erbB1的表达产物,属于酪氨酸激酶生长因子受体家族成员之一,在人类多种实体肿瘤中过度表达,与肿瘤细胞的增殖、侵袭、转移及血管生长等有关[1,2].选择EGFR为靶点是近年来非小细胞肺癌(nonsmallcell lung cancer, NSCLC)治疗的前沿手段,第一代表皮生长因子受体酪氨酸激酶抑制剂(EGFR tyrosine kinaseinhibitors, EGFR-TKIs)吉非替尼或者厄洛替尼对于复发或者进展期NSCLC显示出良好疗效,但耐药现象的存在是临床面临的一大难题.部分患者存在EGFR-TKIs初始耐药,几乎所有治疗有效的病例在经过一定时间的缓解期后也出现疾病进展.EGFR-TKIs耐药涉及多种机制,本文就目前NSCLC中存在的可能机制及其新处理策略作一综述.
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表皮生长因子受体酪氨酸激酶突变对于非小细胞肺癌疗效影响的研究进展
随着肺癌发病机制研究的深入,靶向治疗在NSCLC治疗中的地位日渐重要.其中,以厄洛替尼和吉非替尼为代表的表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor tyrosine kinase inhibitor,EGFR TKI)的靶向药物取得了一定的疗效.