Multiple mutations in the EGFR gene are a major cause for the failure of Erlotinib and Gefitinib in the treatment of patients harboring non-small-cell lung cancer (NSCLC) who initially responded to this therapy. The development of these tyrosine kinase inhibitors (TKIs) is going back to the early 90s, where cancer was widely considered and fully treated as a disease of an organ. Fundamental gain of knowledge in cell biology in general and cancer genetics in particular led us to where we currently stand: cancer is a disease that originates in the genome. Fast and affordable gene sequencing paved the way and opened our eyes for the genetic instability of many cancers, particularly EGFR driven NSCLC. This might allow highly rational and personal therapies by aiming at a very particular wild type and mutant kinase pattern. However, the paradigm "one disease - one target - one drug" is currently challenged. Both activating and deactivating EGFR mutations are known to render the development of novel targeted drugs difficult. Among all lung adenocarcinomas, only 20% are driven by EGFR and only a subpopulation has an activating mutation (e.g. L858R), making them sensitive to first generation EGFR inhibitors. Unfortunately, most of them acquire second deactivating mutations (e.g. T790M) during treatment, leading to a complete loss of response. Are specific inhibitors of the double EGFR mutant L858R/T790M the magic bullet? Much scientific evidence but also high expectations justify this approach. Structural biology of EGFR mutants constitutes the basis for highly rational approaches. Second generation pan EGFR inhibitors inhibiting wild type (WT) and mutant EGFR like Afatinib suffer from dose-limiting adverse effects. Inhibition of WT EGFR is considered to be the culprit. Third generation EGFR inhibitors follow two strategies. Mutant selectivity and improved target residential time. These inhibitors display high mutant selectivity and irreversible binding patterns while sparing WT EGFR activity, hence enhancing tumor selectivity while minimizing adverse effects. Third generation EGFR inhibitors are still undergoing preclinical and clinical evaluation. The most advanced are Rociletinib and AZD9291 which displayed encouraging preliminary clinical phase II data regarding response and adverse effects. In the current review we show both a medicinal chemists' approach toward the design of third generation EGFR inhibitors as well as a detailed overview of the development of EGFR inhibitors over the last decade. High interdisciplinary approaches, such as structural biology and time-resolved tumor genetics pave the way toward the development of drugs that target EGFR mutants. This might lead to highly effective targeted and personalized therapies with enhanced response rates for a minor cohort of patients which have to undergo continuous gene sequencing, hence enabling therapies with tailor-made TKIs.

中文翻译：

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对抗癌症耐药性：突变特异性EGFR抑制剂的机遇和挑战。

EGFR基因的多重突变是厄洛替尼和吉非替尼治疗最初对这种疗法有反应的非小细胞肺癌（NSCLC）患者治疗失败的主要原因。这些酪氨酸激酶抑制剂（TKIs）的发展可以追溯到90年代初，在那里癌症被广泛认为并被完全视为一种器官疾病。基本的细胞生物学知识尤其是癌症遗传学知识的获得使我们进入了目前的状况：癌症是一种起源于基因组的疾病。快速且负担得起的基因测序为许多癌症，尤其是EGFR驱动的NSCLC的基因不稳定性铺平了道路，并为我们打开了眼界。通过针对非常特殊的野生型和突变型激酶模式，这可能允许高度合理的个人治疗。但是，范式“ 抑制野生型（WT）和突变型EGFR（如阿法替尼）的第二代泛EGFR抑制剂遭受剂量限制的副作用。WT EGFR的抑制被认为是罪魁祸首。第三代EGFR抑制剂遵循两种策略。突变选择性和改进的目标停留时间。这些抑制剂在保留WT EGFR活性的同时显示出高的突变选择性和不可逆的结合模式，从而增强了肿瘤的选择性，同时最大程度地减少了不良反应。第三代EGFR抑制剂仍在进行临床前和临床评估。最先进的是Rociletinib和AZD9291，它们显示出令人鼓舞的关于反应和不良反应的初步临床II期数据。在当前的评论中，我们展示了两位药物化学家的 设计第三代EGFR抑制剂的方法以及最近十年EGFR抑制剂发展的详细概述。高度跨学科的方法，例如结构生物学和时间分辨的肿瘤遗传学，为开发针对EGFR突变体的药物铺平了道路。对于那些需要进行连续基因测序的少数人群，这可能会导致高效的针对性和个性化疗法，并提高应答率，从而可以使用量身定制的TKI进行治疗。