新型非小细胞肺癌靶向治疗药吉非替尼的研究进展

吉非替尼是一种表皮生长因子受体(EGFR)酪氨酸激酶抑制剂,对晚期非小细胞肺癌的治疗在一定范围内有显著的效果,而EGFR突变有望成为吉非替尼敏感性的预测指标。国内外临床和基础研究有助于对吉非替尼的合理使用奠定坚实基础。     

第三代EGFR酪氨酸激酶抑制剂在非小细胞肺癌临床治疗中的应用及研究进展

表皮生长因子受体(EGFR)是非小细胞肺癌(NSCLC)靶向治疗最重要的靶点之一。目前,靶向EGFR突变的酪氨酸激酶抑制剂(TKIs)已发展至第三代,广泛用于治疗伴有EGFR敏感突变和伴有EGFR T790M耐药突变的NSCLC患者。然而,第三代EGFR TKIs用药过程中不可避免地会出现继发耐药,限制了该类药物的长期使用和临床治疗预后。本文首先围绕已上市或处于临床研究的第三代EGFR TKIs,重点综述了它们的作用特点和临床疗效。其次,从EGFR依赖性耐药和EGFR非依赖性耐药两个方面,归纳了第三代EGFR TKIs发生继发耐药的潜在机制。最后,针对EGFR依赖性耐药、EGFR非依赖性耐药和机制不明确的耐药,分别总结了可能有效的后续用药策略,以期为以EGFR为靶点的药物开发和临床应用提供借鉴和参考。     

表皮生长因子受体酪氨酸激酶抑制剂对骨组织的影响研究进展★

表皮生长因子受体（EGFR）是原癌基因c-erbB-1的表达产物，具有酪氨酸激酶活性。EGFR与配体结合可以激活下游信号通路并导致肿瘤细胞的增殖及侵袭。在肿瘤细胞中，EGFR过度表达可以激活骨吸收过程，导致肿瘤骨转移。表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）主要包括吉非替尼、厄洛替尼、阿法替尼、奥希替尼等，这些药物可以抑制骨吸收和肿瘤骨转移，但也会导致骨形成障碍。联合用药可以解决耐药等问题，并改善药物对骨组织的影响。本文对常见的EGFR-TKIs在骨形成、骨吸收和肿瘤骨转移等过程中对骨组织的影响及其机制进行综述，对不同EGFR-TKIs联合用药的优点及其对骨组织的影响进行归纳，并就EGFR-TKIs对骨组织负面影响的解决方案进行展望。     

二代表皮生长因子受体酪氨酸激酶抑制剂在非小细胞肺癌中的应用

抑制表皮生长因子受体(EGFR)的信号传导通路是治疗非小细胞肺癌(NSCLC)的有效策略。现在临床上应用的主要是酪氨酸激酶抑制剂(TKIs)的第一代产品-吉非替尼(Gefitinib)和埃罗替尼(erlotinib)。临床前和早期临床试验已经证明第二代TKIs可以提高患者的生存率。因此,本文重点讨论治疗NSCLC最具发展前途的四种第二代TKIs:EKB-569、HKI-272、CI-1033和ZD-6474。     

ROS1重排阳性晚期肺癌患者使用克唑替尼靶向治疗用药分析1例

<正>随着分子医学进展和靶向药物的不断涌现,晚期非小细胞肺癌(NSCLC)的治疗已进入到个体化时代。表皮生长因子受体(EGFR)是东亚裔腺癌的主要驱动基因,发生率高达60.5%,ROSl是另一种酪氨酸激酶受体基因的融合形式,是新近发现的NSCLC驱动基因,在NSCLC患者中的发生率约为1%~[1]。克唑替尼(crizotinib)是多靶点酪氨酸激酶抑制剂~[2-4],于2011年获美国食品和药物     

NSCLC的EGFR突变和基因扩增:从分子水平解析吉非替尼试验(IDEAL/INTACT)结果

目的:大多数用吉非替尼治疗非小细胞肺癌(NSCLC)效果显著的案例,他们的表皮生长因子受体(EGFR)都有特殊的活化突变,但是这些突变的临床预测价值尚未经大规模临床试验证实。本研究的目的是确定EGFR分子水平的变异对吉非替尼在Ⅱ期(IDEAL)和Ⅲ期(INTACT)研究当中缓解率和生存率的影响。患者及方法:我们分析了IDEAL和INTACT试验中肺癌样本发生EGFR突变的频数并将其与EGFR基因扩增棗NSCLC的另一遗传异常作比较。结果:EGFR突变与已确认的吉非替尼治疗NSCLC的临床反应特点有关,包括腺癌、无抽烟史、女性和亚裔在内的人群E…     

治疗非小细胞肺癌新药阿法替尼的研究进展

目的评价治疗非小细胞肺癌新药阿法替尼的作用机制、药效学、安全药理学、毒理学、临床药动学和临床疗效。方法查阅相关文献15篇。结果与结论阿法替尼是表皮生长因子受体(epidermal grow th factor receptor,EGFR)和人表皮生长因子受体2(human epidermalgrow th factor receptor-2,HER2)酪氨酸激酶的强效、不可逆的双重抑制剂,作为伴有EGFR突变的肺癌患者一线治疗药物,疗效优于标准化疗方案,对吉非替尼和厄洛替尼耐药的非小细胞肺癌患者具有较好的临床获益。     

EGFR抑制剂耐药机制研究的新进展

表皮生长因子受体(EGFR)通路在肿瘤发生、发展过程中起到非常重要的作用,它已成为肿瘤分子治疗领域最主要的研究和开发靶点之一。目前有单克隆抗体与小分子受体酪氨酸激酶抑制剂两类EGFR抑制剂在临床治疗中取得成功。然而,该类药物在临床前研究及临床治疗中已经出现耐药现象。由于EGFR调节多种细胞功能,该耐药现象可能与多个传导通路紊乱有关,包括配体自分泌/旁分泌的产生、受体突变、下游信号蛋白的组成性活化以及旁路信号途径的激活。本文就EGFR抑制剂耐药机制的最新研究进展进行综述。     

埃克替尼治疗非小细胞肺癌的研究进展

埃克替尼是我国第一个自主创新的小分子靶向抗癌药,用于表皮生长因子受体(EGFR)基因敏感突变的局部晚期或转移性非小细胞肺癌(NSCLC)患者的治疗,是我国继吉非替尼后第二个用于该适应证的一线药物.2021年6月,埃克替尼单药作为Ⅱ～ⅢA期伴有EGFR敏感突变NSCLC术后辅助治疗的新适应证获批上市,成为第一个用于此类型...     

拉帕替尼有望成为转移性乳腺癌的一线治疗药物

据Scrip近日披露,葛兰素史克（GlaxoSmith Kline,GSK）公司已同时在美国和欧盟提交了申请文件,拟将其治疗乳腺癌的药物拉帕替尼（lapatinib,商品名：Tykerb／Tyverb）作为一线治疗药物,用于那些对激素治疗敏感的转移性乳腺癌患者。拉帕替尼是酪氨酸激酶受体HER2和EGFR的小分子抑制剂,为新型的乳腺癌双靶向治疗药,     

Strategies to overcome resistance to tyrosine kinase inhibitors in non-small-cell lung cancer

The use of molecularly targeted agents has dramatically improved the prognosis of defined subsets of patients with non-small-cell lung cancer harboring somatically activated oncogenes, such as mutant EGFR or rearranged ALK. However, after initial marked responses to EGFR or ALK tyrosine kinase inhibitors (TKIs), almost all patients inevitably progress due to development of acquired resistance. Multiple molecular mechanisms of resistance have been identified; the best characterized are secondary mutations in the tyrosine kinase domain of the oncogene, such as T790M in EGFR and L1196M in ALK, which prevent target inhibition by the corresponding TKI. Other mechanisms include copy number gain of the ALK fusion gene and the activation of bypass signaling pathways that can maintain downstream proliferation and survival signals despite inhibition of the original drug target. Here, the authors provide an overview of the known mechanisms of resistance to TKIs and outline the therapeutic strategies, including new investigational agents and targeted therapies combinations, that have been developed to overcome resistance.     

Resistance to epidermal growth factor receptor-targeted therapy.

The epidermal growth factor receptor (EGFR) has been a major target of molecular anticancer therapy. Two approaches have been developed, involving monoclonal antibodies and receptor tyrosine kinase inhibitors, and both have demonstrated benefit in clinical trials. However, evidence of resistance to these drugs has been described. Cellular levels of EGFR do not always correlate with response to the EGFR tyrosine kinase inhibitors, indicating acquired resistance to these drugs. Since EGFR antagonists interfere with the activation of several intracellular pathways that control cell proliferation, survival, apoptosis, angiogenesis, invasion and metastasis, acquired resistance can occur as a result of several different molecular mechanisms: autocrine/paracrine production of ligand, receptor mutation, constitutive activation of the downstream pathway and activation of alternative pathways. We will describe here potential mechanisms that can cause resistance to EGFR-targeted drugs. Combinations of EGFR antagonists with inhibitors targeting different signaling mechanism(s) - such as insulin-like growth factor receptor and vascular endothelial growth factor receptor - that share the same downstream mediator (e.g., phosphatidylinositol 3-kinase/Akt, mitogen-activated protein kinase), may circumvent or delay the development of resistance to EGFR antagonists resulting in enhanced antitumor activities.     

Mechanisms of acquired resistance to tyrosine kinase inhibitors

In recent years, structural and functional studies reveal that tyrosine kinases (TKs) act as the essential components of signal transduction pathways that regulate cancer cell proliferation, apoptosis and angiogenesis, and therefore become potential targets for anticancer therapy. Most of TK inhibitors (TKIs) are small molecular and hydrophobic compounds, thus they can rapidly reach their specific intracellular targets and inhibit the activation of the related TKs. Unfortunately, accompanied with patients who gain great benefit of TKIs therapy, increasing evidences of acquired resistance to these agents have been documented. The unveiling point mutations within the kinase domain, gene amplification or overexpression, or modification of signaling pathway have been implicated in drug resistance. Additionally, overexpression of ABC transporters is likely to set stage for resistant development. In this review, we focus on the discussion of the molecular mechanisms of acquired resistance to TKIs therapy. The mechanistic understanding may help to put forward new hypotheses on drug development and design better therapies to overcome TKIs resistance.     

Mechanisms of resistance to epidermal growth factor receptor tyrosine kinase inhibitors in patients with advanced non-small-cell lung cancer: clinical and molecular considerations

Non-Small-Cell Lung Cancer (NSCLC) with somatic mutations of the epidermal growth factor receptor (EGFR) is anticipated to respond to small-molecule tyrosine kinase inhibitors (TKIs) of the EGFR tyrosine kinase. There are, however, patients with EGFR mutated tumors who do not demonstrate tumor response. The most widely accepted mechanism of 'de novo' (inherent) resistance to these TKIs involves mutations of the KRAS gene. KRAS is a downstream mediator of EGFR-induced cell signaling, such mutations appear to be mutually exclusive from EGFR mutations in lung cancer. The first molecular modifier of resistance identified in patients who developed resistance (termed 'acquired resistance') to TK inhibition was a new acquired somatic EGFR mutation (T790M). Today there is an ever-growing series of molecular events that have recently come to the forefront to explain other instances of TKI resistance not attributable to T790M or KRAS. These include a number of molecules that interact with EGFR or form part of its downstream signaling pathway such as HER-2, IGFR-1, MET and B-RAF. Considering that the majority of studies carried out to date with respect to the identification of resistant clones have not used highly sensitive techniques (e.g. allelic discrimination to identify somatic mutations), coupled with the relatively low number of studies examining multiple molecular markers and the accepted molecular heterogeneity of NSCLC raise question as to the existence of 'acquired' versus 'de-novo' resistance. By examining the current knowledge base with respect to mechanisms of resistance to EGFR TKIs in NSCLC, we explore whether 'acquired' resistance is 'de-novo' resistance in disguise, and discuss the promises and limitations of molecular stratification with respect to strategies incorporating TKIs in the treatment of NSCLC.     

The fibroblast growth factor receptor signaling pathway as a mediator of intrinsic resistance to EGFR-specific tyrosine kinase inhibitors in non-small cell lung cancer

The EGFR has been targeted through the development of selective tyrosine kinase inhibitors (TKIs) that have proven effective in a subset of non-small cell lung cancer (NSCLC) patients, many bearing gain-of-function EGFR mutations or egfr gene amplification. However, the majority (～80–90%) of NSCLC patients do not respond to EGFR-specific TKIs and a high rate of acquired resistance to these therapeutics is observed in those that do respond. Thus, EGFR-specific TKIs will not, as single agents, make a high impact on overall lung cancer survival. A number of studies support the activities of other receptor tyrosine kinase pathways including cMet, IGF-1R and FGFRs as mechanisms for both intrinsic and acquired resistance to EGFR TKIs. While the role of cMet and IGF-1R signaling systems as mechanisms of resistance to EGFR TKIs has been widely reviewed in recent years, the potential role of FGFR-dependent signaling as a mechanism for EGFR TKI resistance has more recently emerged and will be highlighted herein. Due to the high degree of homology of FGFRs with VEGFRs and PDGFRs, FGFR-active TKIs already exist via development of VEGFR-targeted TKIs as angiogenesis inhibitors. Thus, these agents could be rapidly advanced into clinical investigations as FGFR inhibitors, either alone or in combination with TKIs selective for EGFR, cMet or IGF-1R as a means to expand the spectrum of NSCLC patients that can be effectively targeted with TKI-directed therapies.     

Chronicles of EGFR Tyrosine Kinase Inhibitors: Targeting EGFR C797S Containing Triple Mutations

Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase widely expressed in many cancers such as non-small cell lung cancer (NSCLC), pancreatic cancer, breast cancer, and head and neck cancer. Mutations such as L858R in exon 21, exon 19 truncation (Del19), exon 20 insertions, and others are responsible for aberrant activation of EGFR in NSCLC. First-generation EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib have clinical benefits for EGFR-sensitive (L858R and Del19) NSCLC patients. However, after 10-12 months of treatment with these inhibitors, a secondary T790M mutation at the gatekeeper position in the kinase domain of EGFR was identified, which limited the clinical benefits. Second-generation EGFR irreversible inhibitors (afatinib and dacomitinib) were developed to overcome this T790M mutation. However, their lack of selectivity toward wild-type EGFR compromised their clinical benefits due to serious adverse events. Recently developed third-generation irreversible EGFR TKIs (osimertinib and lazertinib) are selective toward driving mutations and the T790M mutation, while sparing wild-type EGFR activity. The latest studies have concluded that their efficacy was also compromised by additional acquired mutations, including C797S, the key residue cysteine that forms covalent bonds with irreversible inhibitors. Because second- and third-generation EGFR TKIs are irreversible inhibitors, they are not effective against C797S containing EGFR triple mutations (Del19/T790M/C797S and L858R/T790M/C797S). Therefore, there is an urgent unmet medical need to develop next-generation EGFR TKIs that selectively inhibit EGFR triple mutations via a non-irreversible mechanism.     

Mechanisms of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors and new therapeutic perspectives in non small cell lung cancer

EGFR somatic mutations define a subset of NSCLCs that are most likely to benefit from EGFR tyrosine kinase inhibitors (TKIs). These tumors are dependent on EGFR-signaling for survival. Recently, tyrosine kinase domain somatic mutations have been approved as criterion to decide first-line therapy in this group of advanced NSCLCs. Anyway, all patients ultimately develop resistance to these drugs. Acquired resistance is linked to a secondary EGFR mutation in about a half of patients. Uncontrolled activation of MET, another tyrosine kinase receptor, has been implicated in neoplastic invasive growth. MET is overexpressed, activated and sometimes mutated in NSCLC cell lines and tumor tissues. MET increased gene copy number has also been documented in NSCLC and has been studied as negative prognostic factor. It has also been found in about 20% of patients developing acquired resistance to TKIs inhibitors. In this group, it seems to display a new mechanism, which is able to mark tumor independence from EGFR signaling. The study of delayed resistance mechanisms could lead to the development of new therapeutic strategies. Different molecular alterations could be specifically targeted in order to extend disease control in this group of NSCLCs with distinct clinical and molecular features. EGFR irreversible inhibitors, MET inhibitors and dual EGFR/VEGFR inhibitors represent one of the most challenging issues in current clinical research. Ongoing clinical trials and future perspectives are discussed.     

Rational combination of targeted therapies as a strategy to overcome the mechanisms of resistance to inhibitors of EGFR signaling

The epidermal growth factor receptor (EGFR) has been widely used as a target for novel anticancer agents, such as blocking antibodies and small molecular weight tyrosine kinase compounds. In spite of recent advances in cancer cell biology, leading to the introduction of clinically active new drugs, such as cetuximab, panitumumab and erlotinib, unfortunately disease control remains unsuccessful due to the presence of constitutive resistance to EGFR inhibitors in most patients and the development of acquired resistance in the responders. A large number of molecular abnormalities in tumor cells seem to partly contribute to their resistance to anti-EGFR therapy: increased angiogenesis, constitutive activation of downstream mediators, overexpression of other tyrosine kinase receptors. Moreover, some mutations in the EGFR receptor kinase domain seem to play a crucial role in determining the sensitivity of cancer cells to specific inhibitors by altering the conformation of the receptor and its activity. The development of rational combinations of anticancer agents and EGFR inhibitors, able to exert synergistic cytotoxic interactions, has been widely accepted and used in both preclinical and clinical studies. Although the failure of large clinical trial based on empirical combination of anti-EGFR and classic chemotherapeutic agents, several preclinical data seems to support the hypothesis that combining EGFR inhibitors and other novel agents could efficiently inhibit tumor growth and overcome intrinsic resistance to a single-agent based therapy. This review focuses on the role of complementary signalling pathways in the development of resistance to EGFR targeting agents and the rationale to combine novel inhibitors as anticancer therapy.     

Everolimus restores gefitinib sensitivity in resistant non-small cell lung cancer cell lines

The epidermal growth factor receptor (EGFR) is a validated target for therapy in non-small cell lung cancer (NSCLC). Most patients, however, either do not benefit or develop resistance to specific inhibitors of the EGFR tyrosine kinase activity, such as gefitinib or erlotinib. The mammalian target of rapamycin (mTOR) is a key intracellular kinase integrating proliferation and survival pathways and has been associated with resistance to EGFR tyrosine kinase inhibitors. In this study, we assessed the effects of combining the mTOR inhibitor everolimus (RAD001) with gefitinib on a panel of NSCLC cell lines characterized by gefitinib resistance and able to maintain S6K phosphorylation after gefitinib treatment.Everolimus plus gefitinib induced a significant decrease in the activation of MAPK and mTOR signaling pathways downstream of EGFR and resulted in a growth-inhibitory effect rather than in an enhancement of cell death. A synergistic effect was observed in those cell lines characterized by high proliferative index and low doubling time. These data suggest that treatment with everolimus and gefitinib might be of value in the treatment of selected NSCLC patients that exhibit high tumor proliferative activity.