RASA1 and NF1 are Preferentially Co-Mutated and Define A Distinct Genetic Subset of Smoking-Associated Non-Small Cell Lung Carcinomas Sensitive to MEK Inhibition.
RASA1 and NF1 are Preferentially Co-Mutated and Define A Distinct Genetic Subset of Smoking-Associated Non-Small Cell Lung Carcinomas Sensitive to MEK Inhibition.
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DOI：
10.1158/1078-0432.ccr-17-2343
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发表时间：
2018-03-15
期刊：
影响因子：
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通讯作者：
Ladanyi M
中科院分区：
文献类型：
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作者：
Hayashi T;Desmeules P;Smith RS;Drilon A;Somwar R;Ladanyi M
Ras-GTP酶激活蛋白（RasGAP），特别是NF 1和RASA 1，介导RAS/MAPK途径的负调控。我们评估了RASA 1突变的NSCLC与NF 1突变病例的临床和分子特征。分析NSCLC的大型基因组数据集[MSKCC的MSK-IMPACT™数据集（n=2004），TCGA组合的肺癌数据集（n=1144）]以定义RASA 1突变的NSCLC的并发突变和临床特征。使用在RASA 1、NF 1或两者中具有RasGAP截短突变的永生化人支气管上皮细胞（HBEC）和NSCLC细胞系进行功能研究。总体而言，约2%的NSCLC具有RASA 1截短突变，并且这种改变在统计学上但不完全与已知的活化EGFR（p=0.02）和KRAS（p=0.02）突变互斥。出乎意料的是，RASA 1截短突变具有与NF 1截短突变共同发生的强烈倾向（p<0.001）。此外，所有伴有RASA 1/NF 1截短突变的患者（16/16）均缺乏其他已知的肺癌驱动因素。HBEC中RASA 1的敲除激活了RAS下游的信号传导并促进细胞生长。相反，RASA 1突变细胞中RASA 1表达的恢复减少了MAPK和PI 3 K信号传导。虽然仅灭活这两种RasGAP之一的细胞系的生长显示出对MEK或PI 3 K抑制剂的中度和可变敏感性，但同时具有RASA 1/NF 1突变的细胞更加敏感（IC 50：0.040μM曲美替尼）。最后，RASA 1和NF 1的同时基因沉默使HBEC和NSCLC细胞对MEK抑制敏感。癌症基因组和功能数据表明，RASA 1/NF 1功能缺失突变是NSCLC中可能对曲美替尼敏感的强促有丝分裂驱动因素。
Ras-GTPase activating proteins (RasGAPs), notably NF1 and RASA1, mediate negative control of the RAS/MAPK pathway. We evaluated clinical and molecular characteristics of NSCLC with RASA1 mutations in comparison with NF1-mutated cases. Large genomic datasets of NSCLC [MSK-IMPACT™ dataset at MSKCC (n=2004), TCGA combined lung cancer dataset (n=1144)] were analyzed to define concurrent mutations and clinical features of RASA1-mutated NSCLCs. Functional studies were performed using immortalized human bronchial epithelial cells (HBECs) and NSCLC lines with RasGAP truncating mutations in RASA1, NF1, or both. Overall, approximately 2% of NSCLCs had RASA1 truncating mutations, and this alteration was statistically, but not completely, mutually exclusive with known activating EGFR (p=0.02) and KRAS (p=0.02) mutations. Unexpectedly, RASA1 truncating mutations had a strong tendency to co-occur with NF1 truncating mutations (p<0.001). Furthermore, all patients (16/16) with concurrent RASA1/NF1 truncating mutations lacked other known lung cancer drivers. Knockdown of RASA1 in HBECs activated signaling downstream of RAS and promoted cell growth. Conversely, restoration of RASA1 expression in RASA1-mutated cells reduced MAPK and PI3K signaling. While growth of cell lines with inactivation of only one of these two RasGAPs showed moderate and variable sensitivity to inhibitors of MEK or PI3K, cells with concurrent RASA1/NF1 mutations were profoundly more sensitive (IC50: 0.040μM trametinib). Finally, simultaneous genetic silencing of RASA1 and NF1 sensitized both HBECs and NSCLC cells to MEK inhibition. Cancer genomic and functional data nominate concurrent RASA1/NF1 loss of function mutations as a strong mitogenic driver in NSCLC which may sensitize to trametinib.