Activation of PI3K/AKT Pathway Is a Potential Mechanism of Treatment Resistance in Small Cell Lung Cancer
Activation of PI3K/AKT Pathway Is a Potential Mechanism of Treatment Resistance in Small Cell Lung Cancer
复制标题
PI 3 K/AKT通路激活是小细胞肺癌耐药的潜在机制
DOI：
10.1158/1078-0432.ccr-21-1943
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发表时间：
2022-02-01
影响因子：
11.5
通讯作者：
Chen, Ming
中科院分区：
文献类型：
--
作者：
Jin, Ying;Chen, Yamei;Chen, Ming
目的：通过比较小细胞肺癌(SCLC)耐药和敏感肿瘤标本中的基因和表型，探讨小细胞肺癌(SCLC)的耐药机制。实验设计：对11例局限期(LS)-SCLC患者初诊和复发的肿瘤标本进行全外显子组测序，并对基线的1,021个肿瘤相关基因和9例LS-SCLC患者的复发样本进行靶向测序。此外，我们对28例化疗耐药和23例化疗敏感的广泛期(ES)-小细胞肺癌患者的肿瘤样本进行了基于无标记质谱学的蛋白质组学研究。结果：基因组分析显示，在LS-SCLC复发时，PI3K/AKT信号通路中的基因富含获得性体细胞突变或高频获得性拷贝数变异。对ES-SCLC队列中差异上调蛋白的通路分析表明，HIF-1信号通路中存在丰富的HIF-1信号通路。重要的是，在62个含有获得性体细胞拷贝数扩增的PI3K/AKT途径基因中，有7个基因富含HIF-1途径。来自公共数据库的SCLC细胞系转录数据分析证实，PI3K/AKT和HIF-1通路在耐药SCLC细胞系中上调。结论：PI3K/AKT通路激活可能是小细胞肺癌耐药的潜在机制之一。这一发现值得进一步研究，并为逆转化疗/放疗耐药性提供了一种可能的方法。
Purpose: Here, we have investigated treatment resistance mechanisms in small cell lung cancer (SCLC) by focusing on comparing the genotype and phenotype in tumor samples of treatment-resistant and treatment-sensitive SCLC.Experimental Design: We conducted whole-exome sequencing on paired tumor samples at diagnosis and relapse from 11 patients with limited-stage (LS)-SCLC and targeted sequencing of 1,021 cancer-related genes on cell-free DNA at baseline and paired relapsed samples from 9 additional patients with LS-SCLC. Furthermore, we performed label-free mass spectrometry-based proteomics on tumor samples from 28 chemo-resistant and 23 chemo-sensitive patients with extensive-stage (ES)-SCLC. The main findings were validated in vitro in chemo-sensitive versus chemo-resistant SCLC cell lines and analyses of transcriptomic data of SCLC cell lines from a public database.Results: Genomic analyses demonstrated that at relapse of LS-SCLC, genes in the PI3K/AKT signaling pathway were enriched for acquired somatic mutations or high-frequency acquired copy-number variants. Pathway analysis on differentially upregulated proteins from ES-SCLC cohort revealed enrichment in the HIF-1 signaling pathway. Importantly, 7 of 62 PI3K/AKT pathway genes containing acquired somatic copy-number amplifications were enriched in HIF-1 pathway. Analyses of transcriptomic data of SCLC cell lines from public databases confirmed upregulation of PI3K/AKT and HIF-1 pathways in chemo-resistant SCLC cell lines. Furthermore, chemotherapy-resistant cell lines could be sensitive to PI3K inhibitors in vitro.Conclusions: PI3K/AKT pathway activation may be one potential mechanism underlying therapeutic resistance of SCLC. This finding warrants further investigation and provides a possible approach to reverse resistance to chemo/radiotherapy.