Oncotargets and Therapy Dovepress Next-generation Egfr/her Tyrosine Kinase Inhibitors for the Treatment of Patients with Non- Small-cell Lung Cancer Harboring Egfr Mutations: a Review of the Evidence
Oncotargets and Therapy Dovepress Next-generation Egfr/her Tyrosine Kinase Inhibitors for the Treatment of Patients with Non- Small-cell Lung Cancer Harboring Egfr Mutations: a Review of the Evidence
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通讯作者：
X. Wang;D. Goldstein;P. Crowe;Jia-Lin Yang
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作者：
X. Wang;D. Goldstein;P. Crowe;Jia-Lin Yang
特此接受本条款。允许非商业用途的工作，没有任何进一步的许可，从多芬医学出版社有限公司，只要工作适当署名。摘要：针对人表皮生长因子受体（EGFR/HER）家族的酪氨酸激酶抑制剂（TKIs）已被引入临床治疗癌症，特别是非小细胞肺癌（NSCLC）。EGFR/HER-TKIs已经有三代。第一代EGFR/HER-TKIs竞争性和可逆地结合EGFR TK结构域的atp结合位点，在选择性的EGFR突变（actEGFRm）、EGFR L858R和EGFR Del19的NSCLC患者中，在安全性、有效性和生活质量方面显示出显著的突破性治疗。然而，由于EGFR T790M突变阻止TKI通过位阻与EGFR的atp口袋结合，所有这些应答者不可避免地在12个月内产生获得性耐药。第二代EGFR/HER-TKIs的开发是为了延长和维持更有效的反应，并克服对第一代EGFR/HER-TKIs的耐药性。它们与第一代EGFR/HER- tkis的不同之处在于，它们与atp结合位点共价结合，不可逆地阻断酶激活，并靶向EGFR/HER家族成员，包括EGFR、HER2和HER4。临床前，这些化合物抑制actEGFRm、EGFR T790M和wtEGFR的酶活化。第二代EGFR/HER-TKIs可适度改善actEGFRm癌症患者的总生存率。然而，它们在克服EGFR T790M耐药方面没有临床活性，主要是由于同时抑制wtEGFR而产生剂量限制性毒性。第三代EGFR/HER-TKIs选择性和不可逆地靶向EGFR T790M和actEGFRm，同时保留wtEGFR。它们对actEGFRm和EGFR T790M对第一代和第二代EGFR- tkis耐药的NSCLC患者有很好的疗效。由于对wtEGFR的抑制作用降低，它们的毒性发生率似乎也较低。目前，第一代EGFR/HER-TKIs吉非替尼和厄洛替尼以及第二代EGFR/HER-TKI阿法替尼已被批准用于actEGFRm转移性NSCLC的一线治疗。本综述将总结和评估EGFR/HER-TKIs近期发展的广泛证据，重点是第二代和第三代EGFR/HER-TKIs在治疗具有EGFR突变的非小细胞肺癌患者中的应用。
hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms Abstract: Tyrosine kinase inhibitors (TKIs) against human epidermal growth factor receptor (EGFR/HER) family have been introduced into the clinic to treat cancers, particularly non-small-cell lung cancer (NSCLC). There have been three generations of the EGFR/HER-TKIs. First-generation EGFR/HER-TKIs, binding competitively and reversibly to the ATP-binding site of the EGFR TK domain, show a significant breakthrough treatment in selected NSCLC patients with activating EGFR mutations (actEGFRm) EGFR L858R and EGFR Del19 , in terms of safety, efficacy, and quality of life. However, all those responders inevitably develop acquired resistance within 12 months, because of the EGFR T790M mutation, which prevents TKI binding to ATP-pocket of EGFR by steric hindrance. The second-generation EGFR/HER-TKIs were developed to prolong and maintain more potent response as well as overcome the resistance to the first-generation EGFR/HER-TKIs. They are different from the first-generation EGFR/HER-TKIs by covalently binding to the ATP-binding site, irreversibly blocking enzymatic activation, and targeting EGFR/HER family members, including EGFR, HER2, and HER4. Preclinically, these compounds inhibit the enzymatic activation for actEGFRm, EGFR T790M , and wtEGFR. The second-generation EGFR/HER-TKIs improve overall survival in cancer patients with actEGFRm in a modest way. However, they are not clinically active in overcoming EGFR T790M resistance, mainly because of dose-limiting toxicity due to simultaneous inhibition against wtEGFR. The third-generation EGFR/HER-TKIs selectively and irreversibly target EGFR T790M and actEGFRm while sparing wtEGFR. They yield promising efficacy in NSCLC patients with actEGFRm as well as EGFR T790M resistant to the first-and second-generation EGFR-TKIs. They also appear to have a lower incidence of toxicity due to the reduced inhibitory effect on wtEGFR. Currently, the first-generation EGFR/HER-TKIs gefitinib and erlotinib and second-generation EGFR/ HER-TKI afatinib have been approved for use as the first-line treatment of metastatic NSCLC with actEGFRm. This review will summarize and evaluate a broad range of evidence of recent development of EGFR/HER-TKIs, with a focus on the second-and third-generation EGFR/ HER-TKIs, in the treatment of patients with NSCLC harboring EGFR mutations.