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 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.