KRAS Mutation Status Is Associated with Enhanced Dependency on Folate Metabolism Pathways in Non–Small Cell Lung Cancer Cells

Moran, Diarmuid M.; Trusk, Patricia B.; Pry, Karen; Paz, Keren; Sidransky, David; Bacus, Sarah S.

doi:10.1158/1535-7163.mct-13-0649

Cited by 64Lung Cancer Treatments and MutationsCancer, Hypoxia, and MetabolismFolate and B Vitamins Research

KRAS Mutation Status Is Associated with Enhanced Dependency on Folate Metabolism Pathways in Non–Small Cell Lung Cancer Cells

Moran, Diarmuid M., Trusk, Patricia B., Pry, Karen, Paz, Keren, Sidransky, David, Bacus, Sarah S.·2014·Molecular Cancer Therapeutics

DOI 10.1158/1535-7163.mct-13-0649

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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. Mol Cancer Ther; 13(6); 1611–24. ©2014 AACR.

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Mutant KRAS induces folate cycle enzymes and aberrant mTOR activation, a regulator of serine synthesis and the folate cycle.
“Mutant KRAS has also been implicated in the induction of enzymes involved in the folate cycle42 and the aberrant activation of mTOR, a key regulator for both serine synthesis and the folate cycle43,44.”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [42]
MTHFD2's relation to MYC has previously been established.
“MTHFD2’s relation to MYC has previously been established.189,216,217”
From A review of small-molecule inhibitors of one-carbon enzymes: SHMT2 and MTHFD2 in the spotlight (2021) · cites this paper as [217]

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Influential
Deacetylation of MTHFD2 by SIRT4 senses stress signal to inhibit cancer cell growth by remodeling folate metabolism
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Targeting Nonsquamous Nonsmall Cell Lung Cancer via the Proton-Coupled Folate Transporter with 6-Substituted Pyrrolo[2,3-d]Pyrimidine Thienoyl Antifolates
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BackgroundInfluential
Molecular Changes of Lung Malignancy in HIV Infection
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Regulation and Therapeutic Targeting of MTHFD2 and EZH2 in KRAS-Mutated Human Pulmonary Adenocarcinoma
Li, Y., Elakad, O., Yao, S., von Hammerstein-Equord, A. F., Hinterthaner, M., Danner, B. C., Ferrai, C., Ströbel, P., Küffer, S., & Bohnenberger, H. (2022) · Metabolites · doi:10.3390/metabo12070652 · Cited by 15 · see citing works
“To test whether PTX resistance in HCC44 can be recovered by KRASG12C inhibition, we incubated HCC44 and H1993 cells with either AMG510 (2 µM), PTX (20 µM), or in combination.”
BackgroundInfluential
Rerouting the drug response: Overcoming metabolic adaptation in KRAS-mutant cancers
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Gene and MicroRNA Perturbations of Cellular Response to Pemetrexed Implicate Biological Networks and Enable Imputation of Response in Lung Adenocarcinoma
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Combining Nelfinavir With Chloroquine Inhibits In Vivo Growth of Human Lung Cancer Xenograft Tumors
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“Previously, Moran and colleagues have already reported that KRAS -mutant cell line depend on enhanced folate metabolism in functional experiments (12).”
Clinical outcomes to pemetrexed-based versus non-pemetrexed-based platinum doublets in patients with KRAS-mutant advanced non-squamous non-small cell lung cancer
Ricciuti, B., Brambilla, M., Cortellini, A., Giglio, A. D., Ficorella, C., Sidoni, A., Bellezza, G., Crinò, L., Ludovini, V., Baglivo, S., et al. (2019) · Clinical & Translational Oncology · doi:10.1007/s12094-019-02175-y · Cited by 8 · see citing works
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Background
MTHFD2 is required for DNA repair and implicated in LUAD radiotherapy resistance
Huang, Q., Ouyang, W., Su, S., Ma, Z., Hu, Y., Geng, Y., Chen, X., Li, Q. L., Yang, W., & Lu, B. (2026) · Journal of Translational Medicine · doi:10.1186/s12967-026-07680-7 · Cited by 2 · see citing works
“While previous studies have predominantly characterized MTHFD2 through its canonical dehydrogenase activity in tumorigenesis [45, 46], our findings reveal a previously unrecognized role of this metabolic enzyme in DNA damage response pathways.”
Placing purines in precision medicine: Targeting a metabolic reliance in KRAS-mutant tumors
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Abstract B25: KRAS mutation status is associated with enhanced dependency on purine biosynthesis and related pathways in non small cell lung cancer cells
Moran, D. M., Trusk, P. B., Pry, K. J., Paz, K., Sidransky, D., & Bacus, S. S. (2014) · Molecular Cancer Research · doi:10.1158/1557-3125.rasonc14-b25
Self-citation
Abstract 4410: KRAS mutation status is associated with enhanced dependency on purine biosynthesis and related pathways in non small cell lung cancer cells
Moran, D. M., Trusk, P. B., Pry, K. J., Sidransky, D., Paz, K., & Bacus, S. S. (2014) · Cancer Research · doi:10.1158/1538-7445.am2014-4410
Self-citation
Abstract LB-449: KRAS mutation and amplification status predicts sensitivity to antifolate therapies in non-small-cell lung cancer
Moran, D. M., Trusk, P. B., Shell, S. A., Camidge, D. R., Doebele, R. C., Berge, E. M., Vincent, M. D., & Bacus, S. S. (2012) · Cancer Research · doi:10.1158/1538-7445.am2012-lb-449 · Cited by 3 · see citing works
Self-citation
Abstract PR-2: KRAS mutation and amplification status predicts sensitivity to antifolate therapies in non-small cell lung cancer.
Bacus, S. S. (2011) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.targ-11-pr-2 · Cited by 4 · see citing works
Self-citation
Efficacy of platinum-based chemotherapy in EGFR WT nonsquamous advanced non-small cell lung cancer (NSCLC) patients: association with KRAS mutation and thymidylate synthase (TS) levels
Ricciuti, B., Chiari, R., Tofanetti, F. R., Giglio, A. D., Porreca, R., Brambilla, M., Sperduti, I., Bellezza, G., Mencaroni, C., Siggillino, A., et al. (2017) · Annals of Oncology · doi:10.1093/annonc/mdx426.013

Authors: Moran, D. M., Trusk, P. B., Pry, K., Paz, K., Sidransky, D., & Bacus, S. S.
Affiliations: Johns Hopkins University (US)
ORCID: Moran, Diarmuid M.
Pry, Karen
Sidransky, David
Venue: Molecular Cancer Therapeutics
Publisher: American Association for Cancer Research (AACR)
Published: 2014-06-01
Volume: 13
Issue: 6
Pages: 1611-1624
ISSN: 1535-7163 (ISSN-L)
1538-8514
DOI: 10.1158/1535-7163.mct-13-0649
OpenAlex: W2143814205
Cited by: 64
References: 43
Citations by year: 2026: 2 · 2025: 3 · 2024: 9 · 2023: 4 · 2022: 8 · 2021: 9 · 2020: 6 · 2019: 3 · 2018: 9 · 2017: 4 · 2016: 4 · 2015: 1 · 2014: 2
FWCI: 2.94
Type: journal article
Language: en
Open access: closed
Locations: Molecular Cancer Therapeutics (publishedVersion)
PubMed (publishedVersion)
Funders: London Health Sciences Centre
Topics: Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Health Sciences › Medicine › Rheumatology › Folate and B Vitamins Research
Keywords: KRAS mutation, non-small cell lung cancer, folate metabolism, pemetrexed, methotrexate, MYC transcription, purine biosynthesis, MTHFD2, cancer metabolism
MeSH terms: Animals, Carcinoma, Non-Small-Cell Lung, Folic Acid, Humans, Methylenetetrahydrofolate Dehydrogenase (NADP), Mutation, Proto-Oncogene Proteins, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins p21(ras), ras Proteins, Xenograft Model Antitumor Assays, Cell Line, Tumor, Cell Proliferation, Mice

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KRAS Mutation Status Is Associated with Enhanced Dependency on Folate Metabolism Pathways in Non–Small Cell Lung Cancer Cells

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