Kimura Ryo, Adachi Yuta, Hirade Kentaro, Kisoda Satoru, Yanase Shogo, Shibata Noriko, Ishii Makoto, Fujiwara Yutaka, Yamaguchi Rui, Fujita Yasuko, Hosoda Waki, Ebi Hiromichi
Division of Molecular Therapeutics, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan.
Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
Cancers (Basel). 2024 Oct 16;16(20):3501. doi: 10.3390/cancers16203501.
BACKGROUND/OBJECTIVES: Although tyrosine kinase inhibitors (TKIs) targeting EGFR-activating mutations significantly improved the outcome of EGFR-mutant NSCLC, resistance inevitably emerges. Despite the heterogeneity of these resistance mechanisms, many induce activation of MAPK signaling in the presence of EGFR-TKIs. While gene amplification is identified as a resistance mechanism that activates MAPK signaling by directly interacting with RAS, little is known about its clinicopathologic characteristics.
We conducted a single-center retrospective analysis of the presence of amplification in re-biopsied samples in patients with EGFR-mutant NSCLC resistant to EGFR-TKIs. Demographic data, treatment course, and clinical molecular testing reports were extracted from electronic medical records. amplification was determined using a gene copy number assay. RNA sequence analysis was performed in patients with amplification as well as presenting histologic transformations to small-cell lung carcinoma (SCLC).
amplification was identified in five of ninety-seven patients resistant to erlotinib or gefitinib, and four of forty-eight patients resistant to Osimertinib. amplification was dominantly observed in female patients with EGFR exon 19 deletion. All -amplified tumors retained their founder EGFR mutation and were absent of secondary mutations. Two cases were found where amplification correlated with a histological transformation to SCLC.
amplification was identified in 5-8% of EGFR-TKI-resistant tumors. The possible roles of ARAF in SCLC transformation warrant further investigation.
背景/目的：尽管针对表皮生长因子受体（EGFR）激活突变的酪氨酸激酶抑制剂（TKIs）显著改善了EGFR突变型非小细胞肺癌（NSCLC）的治疗效果，但耐药仍不可避免地出现。尽管这些耐药机制具有异质性，但许多机制在存在EGFR-TKIs的情况下会诱导丝裂原活化蛋白激酶（MAPK）信号通路的激活。虽然基因扩增被认为是一种通过与RAS直接相互作用激活MAPK信号通路的耐药机制，但其临床病理特征却知之甚少。
我们对EGFR-TKI耐药的EGFR突变型NSCLC患者再次活检样本中的基因扩增情况进行了单中心回顾性分析。从电子病历中提取人口统计学数据、治疗过程和临床分子检测报告。使用基因拷贝数测定法确定基因扩增情况。对存在基因扩增以及出现向小细胞肺癌（SCLC）组织学转化的患者进行RNA序列分析。
在97例对厄洛替尼或吉非替尼耐药的患者中，有5例检测到基因扩增；在48例对奥希替尼耐药的患者中，有4例检测到基因扩增。基因扩增主要在伴有EGFR外显子19缺失的女性患者中观察到。所有基因扩增的肿瘤均保留其初始EGFR突变，且无继发突变。发现2例基因扩增与向SCLC的组织学转化相关。
在5%-8%的EGFR-TKI耐药肿瘤中检测到基因扩增。ARAF在SCLC转化中的可能作用值得进一步研究。
