AYVM to AYMM transition on HER2 exon 20 insertion induces TKI resistance in NSCLC
(Journal of Thoracic Oncology, IF: 21.1)
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Shiqi Mao, Xinyu Liu, Lin Wang, Yan Wang, Shuo Yang, Tao Jiang, Xingya Li,Qiming Wang, Xuefei Li, Fengying Wu, Guanghui Gao, Xiaoxia Chen, ChunyanWu, Wei Zhang, Jiao Zhang, Xiang Lin, Xiaoyu Zhu, Baobin Li, Fei Li, Caicun Zhou,Shengxiang Ren
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CORRESPONDENCE TO: [email protected]
Pyrotinib, a novel pan-HER tyrosine kinase inhibitor, has demonstrated substantial anti-tumor activity in non-small cell lung cancer (NSCLC) patients harboring HER2 mutations. However, the inevitable resistance to pyrotinib necessitates an in-depth understanding of the underlying mechanisms. In this study, potential resistance-associated mutations were identified through genomic sequencing of clinically paired samples and were validated using in vitro and in vivo models. The cohort for this study comprised 40 patients with paired baseline and resistance samples. Analysis of novel mutations upon the development of resistance did not identify any predominant secondary HER2 mutations. Nevertheless, 12 secondary HER2 mutations (38.7%) occurred either as single nucleotide variations (SNVs, 75%) or insertions/deletions (Indels, 25%), based on HER2 p.Y772_P775dup mutation. Only two mutations led to HER2 autophosphorylation and IL3-independent proliferation of Ba/F3 cells from the in vitro experiments, implying that the remaining 10 secondary mutations were passenger mutations. Further in vivo and in vitro validation showed that the HER2 p.E770_A771insAYMM mutation significantly diminished the sensitivity of murine HER2 mutant lung adenocarcinoma cell line to pyrotinib, with ineffective inhibition of HER2 and its downstream pathways. Drug screening indicated that mobocertinib and dacomitinib could effectively restrain the growth of tumors bearing the HER2 p.E770_A771insAYMM mutation. In summary, our findings unveil a new form of resistance—a secondary mutation superimposed on the original mutation—and offer insights into a potentially sequential strategy for overcoming resistance to pyrotinib.
Pyrotinib是一种新型泛-HER酪氨酸激酶抑制剂，在携带HER2突变的非小细胞肺癌患者中显示出显著的抗肿瘤活性。然而，对Pyrotinib不可避免的耐药性需要深入了解其潜在机制。在这项研究中，通过临床配对样本的基因组测序鉴定了潜在的耐药性相关突变，并使用体外和体内模型进行了验证。本研究的队列由40名患者组成，他们有配对的基线和耐药性样本。对出现耐药性时的新突变的分析没有发现任何主要的继发性HER2突变。然而，根据HER2 p.Y772_P775dup突变，12个继发性HER2突变（38.7%）要么是单核苷酸变异（SNVs，75%），要么是插入/缺失（Indels，25%）。在体外实验中，只有两个突变导致Ba/F3细胞的HER2自磷酸化和IL3非依赖性增殖，这意味着其余10个次级突变是乘客突变。进一步的体内和体外验证表明，HER2 p.E770_A771insAYMM突变显著降低了小鼠HER2突变肺腺癌细胞系对Pyrotinib的敏感性，对HER2及其下游途径的抑制无效。药物筛选表明，Mobocertinib和Dacomitinib能有效抑制携带HER2 p.E770_A771insAYMM突变的肿瘤的生长。总之，我们的发现揭示了一种新的耐药形式——叠加在原始突变上的二次突变——并为克服对Pyrotinib耐药性的潜在序贯策略提供了见解。
文章《
AYVM to AYMM transition on HER2 exon 20 insertion induces TKI resistance in NSCLC》研究了HER2外显子20插入突变中，氨基酸序列从AYVM变为AYMM如何导致非小细胞肺癌（NSCLC）对酪氨酸激酶抑制剂（TKI）的耐药性。
• HER2外显子20插入突变在NSCLC中较为常见，且通常对传统TKI治疗产生耐药性。
• 探讨HER2外显子20插入突变中，AYVM序列变为AYMM序列如何影响TKI治疗的效果。
• 通过细胞实验和临床数据分析，评估AYVM到AYMM的转变对TKI敏感性的影响。
• AYVM到AYMM的转变导致HER2构象的改变，降低了TKI与HER2的结合效率。
• 这种序列变化使得NSCLC细胞对常用TKI（如厄洛替尼、吉非替尼）产生耐药性。
• HER2外显子20插入突变中的AYVM到AYMM转变是导致TKI耐药的关键因素之一。
• 针对这种特定突变的治疗策略需要进一步研究，以克服耐药性。
该研究强调了在NSCLC治疗中，了解特定HER2突变类型对于选择有效的TKI治疗方案的重要性。
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