Small cell transformation of ROS1 fusion-positive lung cancer resistant to ROS1 inhibition
Small cell transformation of ROS1 fusion-positive lung cancer resistant to ROS1 inhibition
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DOI：
10.1038/s41698-020-0127-9
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发表时间：
2020-08-03
影响因子：
7.9
通讯作者：
Shaw, Alice T.
中科院分区：
文献类型：
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作者：
Lin, Jessica J.;Langenbucher, Adam;Shaw, Alice T.
据报道，从非小细胞肺癌向小细胞肺癌的组织学转化是 EGFR 突变和 ALK 融合阳性肺癌靶向治疗的耐药机制。小细胞转化是否发生在其他癌基因驱动的肺癌中仍不清楚。在这里，我们分析了从一名晚期 ROS1 融合阳性肺癌患者身上收集的 2 个死前和 11 个死后转移性肿瘤的基因组图谱，该患者已连续接受 ROS1 抑制剂治疗。尸检时在所有转移部位均观察到小细胞转化的证据，RB1 和 TP53 失活，ROS1 融合表达缺失。全外显子组测序显示出最小的突变和拷贝数异质性，暗示着“硬”克隆扫描。尸检生成的患者衍生模型保留了与小细胞肺癌一致的特征，并表现出对 ROS1 抑制剂的耐药性。该病例支持小细胞转化作为一种反复出现的耐药机制，并强调了阐明其生物学以扩大治疗机会的重要性。
Histologic transformation from non-small cell to small cell lung cancer has been reported as a resistance mechanism to targeted therapy inEGFR-mutant andALKfusion-positive lung cancers. Whether small cell transformation occurs in other oncogene-driven lung cancers remains unknown. Here we analyzed the genomic landscape of two pre-mortem and 11 post-mortem metastatic tumors collected from an advanced,ROS1fusion-positive lung cancer patient, who had received sequential ROS1 inhibitors. Evidence of small cell transformation was observed in all metastatic sites at autopsy, with inactivation ofRB1andTP53, and loss ofROS1fusion expression. Whole-exome sequencing revealed minimal mutational and copy number heterogeneity, suggestive of "hard" clonal sweep. Patient-derived models generated from autopsy retained features consistent with small cell lung cancer and demonstrated resistance to ROS1 inhibitors. This case supports small cell transformation as a recurring resistance mechanism, and underscores the importance of elucidating its biology to expand therapeutic opportunities.