| Autor: |
Yuchan Li, Omar Elakad, Sha Yao, Alexander von Hammerstein-Equord, Marc Hinterthaner, Bernhard C. Danner, Carmelo Ferrai, Philipp Ströbel, Stefan Küffer, Hanibal Bohnenberger |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Předmět: |
|
| Zdroj: |
Metabolites, Vol 12, Iss 7, p 652 (2022) |
| Druh dokumentu: |
article |
| ISSN: |
2218-1989 |
| DOI: |
10.3390/metabo12070652 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
|
