Moran Diarmuid M, Trusk Patricia B, Pry Karen, Paz Keren, Sidransky David, Bacus Sarah S
Authors' Affiliations: Translational R&D Oncology Group, Quintiles, Westmont; Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois; Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland; and Champions Oncology, Inc., Hackensack, New Jersey and Baltimore, Maryland
Authors' Affiliations: Translational R&D Oncology Group, Quintiles, Westmont; Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois; Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland; and Champions Oncology, Inc., Hackensack, New Jersey and Baltimore, Maryland.
Mol Cancer Ther. 2014 Jun;13(6):1611-24. doi: 10.1158/1535-7163.MCT-13-0649. Epub 2014 Mar 31.
KRAS gene mutation is linked to poor prognosis and resistance to therapeutics in non-small cell lung cancer (NSCLC). In this study, we have explored the possibility of exploiting inherent differences in KRAS-mutant cell metabolism for treatment. This study identified a greater dependency on folate metabolism pathways in KRAS mutant compared with KRAS wild-type NSCLC cell lines. Microarray gene expression and biologic pathway analysis identified higher expression of folate metabolism- and purine synthesis-related pathways in KRAS-mutant NSCLC cells compared with wild-type counterparts. Moreover, pathway analysis and knockdown studies suggest a role for MYC transcriptional activity in the expression of these pathways in KRAS-mutant NSCLC cells. Furthermore, KRAS knockdown and overexpression studies demonstrated the ability of KRAS to regulate expression of genes that comprise folate metabolism pathways. Proliferation studies demonstrated higher responsiveness to methotrexate, pemetrexed, and other antifolates in KRAS-mutant NSCLC cells. Surprisingly, KRAS gene expression is downregulated in KRAS wild-type and KRAS-mutant cells by antifolates, which may also contribute to higher efficacy of antifolates in KRAS-mutant NSCLC cells. In vivo analysis of multiple tumorgraft models in nude mice identified a KRAS-mutant tumor among the pemetrexed-responsive tumors and also demonstrated an association between expression of the folate pathway gene, methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), and antifolate activity. Collectively, we identify altered regulation of folate metabolism in KRAS-mutant NSCLC cells that may account for higher antifolate activity in this subtype of NSCLC.
KRAS基因突变与非小细胞肺癌（NSCLC）的预后不良和治疗耐药性相关。在本研究中，我们探索了利用KRAS突变细胞代谢的内在差异进行治疗的可能性。本研究发现，与KRAS野生型NSCLC细胞系相比，KRAS突变细胞对叶酸代谢途径的依赖性更强。基因芯片基因表达和生物学通路分析表明，与野生型对应细胞相比，KRAS突变型NSCLC细胞中叶酸代谢和嘌呤合成相关通路的表达更高。此外，通路分析和基因敲低研究表明，MYC转录活性在KRAS突变型NSCLC细胞中这些通路的表达中发挥作用。此外，KRAS基因敲低和过表达研究证明了KRAS调节叶酸代谢途径相关基因表达的能力。增殖研究表明，KRAS突变型NSCLC细胞对甲氨蝶呤、培美曲塞和其他抗叶酸药物的反应性更高。令人惊讶的是，抗叶酸药物可使KRAS野生型和KRAS突变型细胞中的KRAS基因表达下调，这也可能是抗叶酸药物在KRAS突变型NSCLC细胞中疗效更高的原因之一。对裸鼠多种肿瘤移植模型的体内分析在对培美曲塞有反应的肿瘤中发现了KRAS突变肿瘤，并且还证明了叶酸途径基因亚甲基四氢叶酸脱氢酶2（MTHFD2）的表达与抗叶酸活性之间的关联。总体而言，我们发现KRAS突变型NSCLC细胞中叶酸代谢的调节改变，这可能是该亚型NSCLC中抗叶酸活性较高的原因。
