title: KRAS mutation status is associated with enhanced dependency on folate metabolism pathways in non-small cell lung cancer cells.
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.
authors.affiliation: 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 sarah.bacus@quintiles.com diarmuid.moran@quintiles.com.
authors.forename: Diarmuid M
authors.initials: DM
authors.lastname: Moran
authors.affiliation: 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.forename: Patricia B
authors.initials: PB
authors.lastname: Trusk
authors.affiliation: 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.forename: Karen
authors.initials: K
authors.lastname: Pry
authors.affiliation: 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.forename: Keren
authors.initials: K
authors.lastname: Paz
authors.affiliation: 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, MarylandAuthors' 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.forename: David
authors.initials: D
authors.lastname: Sidransky
authors.affiliation: 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, MarylandAuthors' 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 sarah.bacus@quintiles.com diarmuid.moran@quintiles.com.
authors.forename: Sarah S
authors.initials: SS
authors.lastname: Bacus
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005492:Folic Acid / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000378:metabolism; D051379:Mice; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D005492:Folic Acid; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP); D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins