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首页> 美国卫生研究院文献>Translational Lung Cancer Research >Kinase inhibitor-responsive genotypes in EGFR mutated lung adenocarcinomas: moving past common point mutations or indels into uncommon kinase domain duplications and rearrangements
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Kinase inhibitor-responsive genotypes in EGFR mutated lung adenocarcinomas: moving past common point mutations or indels into uncommon kinase domain duplications and rearrangements

机译：EGFR突变的肺腺癌中激酶抑制剂反应性基因型：超越共同点突变或插入缺失进入罕见的激酶结构域重复和重排

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The most frequent epidermal growth factor receptor (EGFR) mutations found by traditional or comprehensive molecular profiling of lung adenocarcinomas include indels of exon 19 (the exon 19 deletion delE746_A750 being the most common) and the exon 21 L858R point mutation. The current approval labels for first line palliative gefitinib 250 mg/day, erlotinib 150 mg/day and afatinib 40 mg/day for advanced lung cancers require the presence of the aforementioned classical/sensitizing EGFR mutations. Other gefitinib, erlotinib and afatinib sensitizing mutations include exon 18 indels, G719X, exon 19 insertions, A763_Y764insFQEA, S768I and L861Q; for which off-label EGFR kinase inhibitor use is generally agreed upon by thoracic oncologists. The main biological mechanism of resistance to approved first line EGFR inhibitors is the selection/acquisition of EGFR-T790M that in itself can be inhibited by osimertinib 80 mg/day, a 3rd generation EGFR inhibitor that is bypassed by EGFR-C797X mutations. Another class of de novo inhibitor insensitive mutation includes EGFR exon 20 insertions. More recently, the dichotomy of only point mutations or indels explaining aberrant kinase activation of EGFR plus inhibitor response has been shattered by the discovery of uncommon (<0.5% of all EGFR mutations) genomic events involving exon 18–25 kinase domain duplications (KDD) and rearrangements (EGFR-RAD51 or EGFR-PURB). The latter lead to oncogene addiction, enhanced sensitivity to kinase inhibitors in vitro and clinical responses to approved EGFR inhibitors. The enhanced landscape of EGFR inhibitor-responsive genotypes highlights that comprehensive molecular profiling may be necessary to maximize the identification of all cases that can benefit from precision oncology.
机译：通过传统或全面的肺腺癌分子谱分析发现的最常见的表皮生长因子受体（EGFR）突变包括第19外显子插入缺失（外显子19缺失delE746_A750最常见）和第21外显子L858R点突变。对于晚期肺癌的一线姑息性吉非替尼250毫克/天，厄洛替尼150毫克/天和阿法替尼40毫克/天的当前批准标签要求存在上述经典/敏化EGFR突变。其他吉非替尼，厄洛替尼和阿法替尼致敏突变包括外显子18 indels，G719X，外显子19插入，A763_Y764insFQEA，S768I和L861Q;胸肿瘤科医生通常同意使用哪种标记外的EGFR激酶抑制剂。对已批准的一线EGFR抑制剂产生抗药性的主要生物学机制是EGFR / T790M的选择/获得，其本身可以被80毫克/天的奥美替尼（一种绕过第三代的EGFR抑制剂）抑制EGFR-C797X突变引起的。另一类从头抑制剂不敏感突变包括EGFR外显子20插入。最近，发现涉及外显子18-25激酶结构域重复（KDD）的罕见基因组事件（占所有EGFR突变的<0.5％），打破了仅点突变或插入缺失的二分法，从而解释了EGFR加抑制剂反应的异常激酶激活。和重排（EGFR-RAD51或EGFR-PURB）。后者导致癌基因成瘾，体外对激酶抑制剂的敏感性增强以及对批准的EGFR抑制剂的临床反应。 EGFR抑制剂反应性基因型的增强态势表明，可能需要全面的分子谱分析，以最大程度地鉴定可从精密肿瘤学中受益的所有病例。

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