文章：

表皮生长因子受体-酪氨酸激酶抑制剂耐药后小细胞肺癌转化肿瘤中的ARAF基因扩增

ARAFAmplification in Small-Cell Lung Cancer-Transformed Tumors Following Resistance to Epidermal Growth Factor Receptor–Tyrosine Kinase Inhibitors

原文发布日期：16 October 2024

DOI: 10.3390/cancers16203501

类型: Article

开放获取: 是

英文摘要：

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. WhileARAFgene amplification is identified as a resistance mechanism that activates MAPK signaling by directly interacting with RAS, little is known about its clinicopathologic characteristics. Methods: We conducted a single-center retrospective analysis of the presence ofARAFamplification 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.ARAFamplification was determined using a gene copy number assay. RNA sequence analysis was performed in patients withARAFamplification as well as presenting histologic transformations to small-cell lung carcinoma (SCLC). Results:ARAFamplification was identified in five of ninety-seven patients resistant to erlotinib or gefitinib, and four of forty-eight patients resistant to Osimertinib.ARAFamplification was dominantly observed in female patients with EGFR exon 19 deletion. AllARAF-amplified tumors retained their founder EGFR mutation and were absent of secondary mutations. Two cases were found whereARAFamplification correlated with a histological transformation to SCLC. Conclusions:ARAFamplification was identified in 5–8% of EGFR-TKI-resistant tumors. The possible roles of ARAF in SCLC transformation warrant further investigation.

摘要翻译： 

背景/目的：尽管针对EGFR激活突变的酪氨酸激酶抑制剂（TKI）显著改善了EGFR突变型非小细胞肺癌（NSCLC）的预后，但耐药性仍不可避免地出现。尽管这些耐药机制具有异质性，但许多机制在EGFR-TKI存在下会诱导MAPK信号通路的激活。虽然ARAF基因扩增已被确定为一种通过与RAS直接相互作用激活MAPK信号通路的耐药机制，但其临床病理特征尚不明确。方法：我们对EGFR-TKI耐药的EGFR突变型NSCLC患者再活检样本中ARAF扩增的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、治疗过程及临床分子检测报告。ARAF扩增通过基因拷贝数检测确定。对存在ARAF扩增且发生小细胞肺癌（SCLC）组织学转化的患者进行了RNA序列分析。结果：在97例厄洛替尼或吉非替尼耐药患者中，有5例检测到ARAF扩增；在48例奥希替尼耐药患者中，有4例检测到ARAF扩增。ARAF扩增主要见于携带EGFR外显子19缺失突变的女性患者。所有ARAF扩增肿瘤均保留了初始EGFR突变，且未出现继发性突变。发现两例ARAF扩增与组织学转化为SCLC相关。结论：ARAF扩增在5–8%的EGFR-TKI耐药肿瘤中被检出。ARAF在SCLC转化中的潜在作用值得进一步研究。

原文链接：

ARAFAmplification in Small-Cell Lung Cancer-Transformed Tumors Following Resistance to Epidermal Growth Factor Receptor–Tyrosine Kinase Inhibitors