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Drug Sensitivity and Allele Specificity of First-Line Osimertinib Resistance EGFR Mutations.
Cancer Research ( IF 11.2 ) Pub Date : 2020-03-19 , DOI: 10.1158/0008-5472.can-19-3819
Jacqueline H Starrett 1 , Alexis A Guernet 2 , Maria Emanuela Cuomo 2 , Kamrine E Poels 3 , Iris K van Alderwerelt van Rosenburgh 4, 5 , Amy Nagelberg 6 , Dylan Farnsworth 6 , Kristin S Price 7 , Hina Khan 8 , Kumar Dilip Ashtekar 4, 5 , Mmaserame Gaefele 9 , Deborah Ayeni 1 , Tyler F Stewart 10 , Alexandra Kuhlmann 11 , Susan M Kaech 12 , Arun M Unni 13 , Robert Homer 1, 14 , William W Lockwood 6 , Franziska Michor 3, 15 , Sarah B Goldberg 9, 10 , Mark A Lemmon 4, 5, 9 , Paul D Smith 16 , Darren A E Cross 17 , Katerina Politi 1, 9, 10
Affiliation  

Osimertinib, a mutant-specific third-generation EGFR tyrosine kinase inhibitor, is emerging as the preferred first-line therapy for EGFR-mutant lung cancer, yet resistance inevitably develops in patients. We modeled acquired resistance to osimertinib in transgenic mouse models of EGFRL858R -induced lung adenocarcinoma and found that it is mediated largely through secondary mutations in EGFR-either C797S or L718V/Q. Analysis of circulating free DNA data from patients revealed that L718Q/V mutations almost always occur in the context of an L858R driver mutation. Therapeutic testing in mice revealed that both erlotinib and afatinib caused regression of osimertinib-resistant C797S-containing tumors, whereas only afatinib was effective on L718Q mutant tumors. Combination first-line osimertinib plus erlotinib treatment prevented the emergence of secondary mutations in EGFR. These findings highlight how knowledge of the specific characteristics of resistance mutations is important for determining potential subsequent treatment approaches and suggest strategies to overcome or prevent osimertinib resistance in vivo. SIGNIFICANCE: This study provides insight into the biological and molecular properties of osimertinib resistance EGFR mutations and evaluates therapeutic strategies to overcome resistance. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/10/2017/F1.large.jpg.

中文翻译:

一线奥希替尼耐药 EGFR 突变的药物敏感性和等位基因特异性。

奥希替尼是一种突变特异性第三代 EGFR 酪氨酸激酶抑制剂,正在成为 EGFR 突变肺癌的首选一线疗法,但患者不可避免地会产生耐药性。我们在 EGFRL858R 诱导的肺腺癌转基因小鼠模型中模拟了对奥希替尼的获得性耐药性,发现它主要通过 EGFR-C797S 或 L718V/Q 中的继发突变介导。对患者循环游离 DNA 数据的分析表明,L718Q/V 突变几乎总是发生在 L858R 驱动突变的背景下。在小鼠中进行的治疗测试表明,厄洛替尼和阿法替尼都能导致对奥希替尼耐药的 C797S 肿瘤消退,而只有阿法替尼对 L718Q 突变肿瘤有效。一线奥希替尼联合厄洛替尼治疗可防止 EGFR 继发突变的出现。这些发现强调了了解耐药突变的具体特征对于确定潜在的后续治疗方法很重要,并提出了克服或预防体内奥希替尼耐药的策略。意义:本研究深入了解奥希替尼耐药 EGFR 突变的生物学和分子特性,并评估克服耐药性的治疗策略。图形摘要:http://cancerres.aacrjournals.org/content/canres/80/10/2017/F1.large.jpg。这些发现强调了了解耐药突变的具体特征对于确定潜在的后续治疗方法很重要,并提出了克服或预防体内奥希替尼耐药的策略。意义:本研究深入了解奥希替尼耐药 EGFR 突变的生物学和分子特性,并评估克服耐药性的治疗策略。图形摘要:http://cancerres.aacrjournals.org/content/canres/80/10/2017/F1.large.jpg。这些发现强调了了解耐药突变的具体特征对于确定潜在的后续治疗方法很重要,并提出了克服或预防体内奥希替尼耐药的策略。意义:本研究深入了解奥希替尼耐药 EGFR 突变的生物学和分子特性,并评估克服耐药性的治疗策略。图形摘要:http://cancerres.aacrjournals.org/content/canres/80/10/2017/F1.large.jpg。
更新日期:2020-05-15
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