Abstract
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.
Highlights
Folates play an important role in many cellular biosynthetic processes and are essential for cell growth and proliferation [1]
Analysis of the relatedness of canonical pathways that share common genes in this dataset identified a network of interrelated metabolic canonical pathways in KRASmut non–small cell lung cancer (NSCLC) cells that converge on purine biosynthesis, folate metabolism, and to a lesser extent glycine biosynthesis (Fig. 1B); and identified genes that are shared by these pathways (Table 1)
We have identified elevated expression of genes associated with purine biosynthesis and folate metabolism in KRAS-mutant NSCLC cells
Summary
Folates play an important role in many cellular biosynthetic processes and are essential for cell growth and proliferation [1]. Folate metabolism is critical for the biosynthesis of amino acids such as methionine and nucleotides, including purines and pyrimidines. Folate is reduced to tetrahydrofolate (THF) in steps that are catalyzed intracellularly by dihydrofolate reductase (DHFR). In an interconnected and dependent pathway, thymidylate synthase (TYMS) maintains cellular thymi-. Authors' Affiliations: 1Translational R&D Oncology Group, Quintiles, Westmont; 2Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois; 3Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland; and 4Champions Oncology, Inc., Hackensack, New Jersey and Baltimore, Maryland. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/). D.M. Moran and P.B. Trusk contributed to this work
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