MTHFD2 marks pemetrexed resistance in pulmonary adenocarcinoma with EGFR wild type

PURPOSE: Lung cancer is the leading cause of cancer-related deaths worldwide. Patients with an amplification of the MTHFD2 gene have a particularly poor prognosis. MTHFD2 signaling has been associated with migration, metastasis, and proliferation of lung cancer cells mediated through ERK signaling. Although the enzymatic activity of the MTHFD2 protein is well understood, little is known about its larger role in chemoresistance. METHODS: Seventy-nine of non-small cell lung cancer (NSCLC) samples with clinical follow-up were subjected to immunohistochemical staining for MTHFD2 and sequenced using next generation sequencing (NGS) to determine EGFR status. MTHFD2 gene was knocked down in two NSCLC cell lines with wild type EGFR gene (HCC44 and H1993) where MTHFD2 signaling and chemotherapy resistance against pemetrexed were evaluated. RESULTS: MTHFD2 expression data revealed a strong prognosis relevance in adenocarcinoma (LUAD). Immunoblotting of cell lines showed a MTHFD2 dependent and cell type specific ERK signaling in EGFR wild type cells. MTHFD2 expression induced proliferation of NSCLC cells and their resistance against pemetrexed. Knocking down the MTHFD2 gene induced cycle arrest, however, it did not activate apoptosis signaling within HCC44 cell line. CONCLUSIONS: MTHFD2 expression is strongly associated with prognosis in LUAD patients, as well as with increased cellular proliferation and resistance to pemetrexed in LUAD patients with wild-type EGFR. These findings suggest that MTHFD2 could serve as a valuable biomarker for predicting treatment outcomes in LUAD. Further studies are needed to fully explore the clinical implications and potential combination therapies targeting MTHFD2 in LUAD.