Small cell lung cancer transformation and T790M mutation: complimentary roles in acquired resistance to kinase inhibitors in lung cancer.
Small cell lung cancer transformation and T790M mutation: complimentary roles in acquired resistance to kinase inhibitors in lung cancer.
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DOI：
10.1038/srep14447
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发表时间：
2015-09-24
影响因子：
4.6
通讯作者：
Mitsudomi T
中科院分区：
文献类型：
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作者：
Suda K;Murakami I;Sakai K;Mizuuchi H;Shimizu S;Sato K;Tomizawa K;Tomida S;Yatabe Y;Nishio K;Mitsudomi T
肺癌通常在表皮生长因子受体（EGFR）基因中存在突变。由于EGFR突变肺癌的增殖和生存仅依赖于突变EGFR的异常信号传导，因此这些肿瘤通常对EGFR酪氨酸激酶抑制剂（TKI）表现出显著的反应。然而，获得对这些药物的耐药性几乎是不可避免的，因此更好地了解潜在的耐药机制至关重要。小细胞肺癌（SCLC）转化是一种相对罕见的获得性耐药机制，最近引起了相当大的关注。在本研究中，通过深入分析从尸检病例中获得的多个EGFR-TKI难治性病变，我们观察到SCLC转化与EGFR T790 M继发突变（耐药突变）之间的互补关系。我们还确定了TKI难治性病变与SCLC转化和EGFR T790 M突变之间遗传畸变的相似性和差异。特别是，靶测序显示在所有治疗前和治疗后病变中存在TP 53 P151 S突变。仅在具有SCLC转化的TKI难治性病变中鉴定了PTEN M264 I突变，而仅在治疗前原发性肿瘤样品中鉴定了PIK 3CA和RB 1突变。这些结果为理解通过SCLC转化获得对EGFR-TKI的抗性提供了基础。
Lung cancers often harbour a mutation in the epidermal growth factor receptor (EGFR) gene. Because proliferation and survival of lung cancers with EGFR mutation solely depend on aberrant signalling from the mutated EGFR, these tumours often show dramatic responses to EGFR tyrosine kinase inhibitors (TKIs). However, acquiring resistance to these drugs is almost inevitable, thus a better understanding of the underlying resistance mechanisms is critical. Small cell lung cancer (SCLC) transformation is a relatively rare acquired resistance mechanism that has lately attracted considerable attention. In the present study, through an in-depth analysis of multiple EGFR-TKI refractory lesions obtained from an autopsy case, we observed a complementary relationship between SCLC transformation and EGFR T790M secondary mutation (resistance mutation). We also identified analogies and differences in genetic aberration between a TKI-refractory lesion with SCLC transformation and one with EGFR T790M mutation. In particular, target sequencing revealed a TP53 P151S mutation in all pre- and post-treatment lesions. PTEN M264I mutation was identified only in a TKI-refractory lesion with SCLC transformation, while PIK3CA and RB1 mutations were identified only in pre-treatment primary tumour samples. These results provide the groundwork for understanding acquired resistance to EGFR-TKIs via SCLC transformation.