Regulation and Therapeutic Targeting of MTHFD2 and EZH2 in KRAS-Mutated Human Pulmonary Adenocarcinoma
Activating KRAS mutations occur in about 30% of pulmonary adenocarcinoma (AC) cases and the discovery of specific inhibitors of G12C-mutated KRAS has considerably improved the prognosis for a subgroup of about 14% of non-small cell lung cancer (NSCLC) patients. However, even in patients with a KRAS...
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MDPI AG
2022-07-01
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| Series: | Metabolites |
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| Online Access: | https://www.mdpi.com/2218-1989/12/7/652 |
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| author | Yuchan Li Omar Elakad Sha Yao Alexander von Hammerstein-Equord Marc Hinterthaner Bernhard C. Danner Carmelo Ferrai Philipp Ströbel Stefan Küffer Hanibal Bohnenberger |
| author_facet | Yuchan Li Omar Elakad Sha Yao Alexander von Hammerstein-Equord Marc Hinterthaner Bernhard C. Danner Carmelo Ferrai Philipp Ströbel Stefan Küffer Hanibal Bohnenberger |
| author_sort | Yuchan Li |
| collection | DOAJ |
| description | Activating KRAS mutations occur in about 30% of pulmonary adenocarcinoma (AC) cases and the discovery of specific inhibitors of G12C-mutated KRAS has considerably improved the prognosis for a subgroup of about 14% of non-small cell lung cancer (NSCLC) patients. However, even in patients with a KRAS G12C mutation, the overall response rate only reaches about 40% and mutations other than G12C still cannot be targeted. Despite the fact that one-carbon metabolism (1CM) and epigenetic regulation are known to be dysregulated by aberrant KRAS activity, we still lack evidence that co-treatment with drugs that regulate these factors might ameliorate response rates and patient prognosis. In this study, we show a direct dependency of Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) and Enhancer of Zeste Homolog 2 (EZH2) expression on mutationally activated KRAS and their prognostic relevance in KRAS-mutated AC. We show that aberrant KRAS activity generates a vulnerability of AC cancer cell lines to both MTHFD2 and EZH2 inhibitors. Importantly, co-inhibition of both factors was synergistically effective and comparable to KRASG12C inhibition alone, paving the way for their use in a therapeutic approach for NSCLC cancer patients. |
| first_indexed | 2024-03-09T13:23:55Z |
| format | Article |
| id | doaj.art-fbc0d3940c5d4cfc9d040a2a25da8309 |
| institution | Directory Open Access Journal |
| issn | 2218-1989 |
| language | English |
| last_indexed | 2024-03-09T13:23:55Z |
| publishDate | 2022-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Metabolites |
| spelling | doaj.art-fbc0d3940c5d4cfc9d040a2a25da83092023-11-30T21:27:27ZengMDPI AGMetabolites2218-19892022-07-0112765210.3390/metabo12070652Regulation and Therapeutic Targeting of MTHFD2 and EZH2 in KRAS-Mutated Human Pulmonary AdenocarcinomaYuchan Li0Omar Elakad1Sha Yao2Alexander von Hammerstein-Equord3Marc Hinterthaner4Bernhard C. Danner5Carmelo Ferrai6Philipp Ströbel7Stefan Küffer8Hanibal Bohnenberger9Institute of Pathology, University Medical Center, 37075 Göttingen, GermanyInstitute of Pathology, University Medical Center, 37075 Göttingen, GermanyInstitute of Pathology, University Medical Center, 37075 Göttingen, GermanyDepartment of Thoracic and Cardiovascular Surgery, University Medical Center, 37075 Göttingen, GermanyDepartment of Thoracic and Cardiovascular Surgery, University Medical Center, 37075 Göttingen, GermanyDepartment of Thoracic and Cardiovascular Surgery, University Medical Center, 37075 Göttingen, GermanyInstitute of Pathology, University Medical Center, 37075 Göttingen, GermanyInstitute of Pathology, University Medical Center, 37075 Göttingen, GermanyInstitute of Pathology, University Medical Center, 37075 Göttingen, GermanyInstitute of Pathology, University Medical Center, 37075 Göttingen, GermanyActivating KRAS mutations occur in about 30% of pulmonary adenocarcinoma (AC) cases and the discovery of specific inhibitors of G12C-mutated KRAS has considerably improved the prognosis for a subgroup of about 14% of non-small cell lung cancer (NSCLC) patients. However, even in patients with a KRAS G12C mutation, the overall response rate only reaches about 40% and mutations other than G12C still cannot be targeted. Despite the fact that one-carbon metabolism (1CM) and epigenetic regulation are known to be dysregulated by aberrant KRAS activity, we still lack evidence that co-treatment with drugs that regulate these factors might ameliorate response rates and patient prognosis. In this study, we show a direct dependency of Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) and Enhancer of Zeste Homolog 2 (EZH2) expression on mutationally activated KRAS and their prognostic relevance in KRAS-mutated AC. We show that aberrant KRAS activity generates a vulnerability of AC cancer cell lines to both MTHFD2 and EZH2 inhibitors. Importantly, co-inhibition of both factors was synergistically effective and comparable to KRASG12C inhibition alone, paving the way for their use in a therapeutic approach for NSCLC cancer patients.https://www.mdpi.com/2218-1989/12/7/652one-carbon metabolismMTHFD2KRASEZH2pulmonary adenocarcinoma |
| spellingShingle | Yuchan Li Omar Elakad Sha Yao Alexander von Hammerstein-Equord Marc Hinterthaner Bernhard C. Danner Carmelo Ferrai Philipp Ströbel Stefan Küffer Hanibal Bohnenberger Regulation and Therapeutic Targeting of MTHFD2 and EZH2 in KRAS-Mutated Human Pulmonary Adenocarcinoma Metabolites one-carbon metabolism MTHFD2 KRAS EZH2 pulmonary adenocarcinoma |
| title | Regulation and Therapeutic Targeting of MTHFD2 and EZH2 in KRAS-Mutated Human Pulmonary Adenocarcinoma |
| title_full | Regulation and Therapeutic Targeting of MTHFD2 and EZH2 in KRAS-Mutated Human Pulmonary Adenocarcinoma |
| title_fullStr | Regulation and Therapeutic Targeting of MTHFD2 and EZH2 in KRAS-Mutated Human Pulmonary Adenocarcinoma |
| title_full_unstemmed | Regulation and Therapeutic Targeting of MTHFD2 and EZH2 in KRAS-Mutated Human Pulmonary Adenocarcinoma |
| title_short | Regulation and Therapeutic Targeting of MTHFD2 and EZH2 in KRAS-Mutated Human Pulmonary Adenocarcinoma |
| title_sort | regulation and therapeutic targeting of mthfd2 and ezh2 in kras mutated human pulmonary adenocarcinoma |
| topic | one-carbon metabolism MTHFD2 KRAS EZH2 pulmonary adenocarcinoma |
| url | https://www.mdpi.com/2218-1989/12/7/652 |
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