Exploiting serine metabolism and the tyrosine kinase inhibitor sorafenib for treating renal cell carcinoma

Renal cell carcinoma (RCC) is the most common urological malignancy, with its global incidence having increased substantially in recent years. The limited efficacy of conventional therapies, including chemotherapy and radiotherapy, contributes to poor clinical outcomes, highlighting the need for a better understanding of the molecular mechanisms underlying RCC progression and treatment resistance. Such insights may facilitate improved patient stratification and the identification of novel therapeutic targets. Here, we identified serine hydroxymethyltransferase 2 (SHMT2) as a key metabolic enzyme involved in cancer-associated metabolic reprogramming and RCC cell proliferation. SHMT2 expression was significantly higher in RCC tissues than in their normal counterparts, and its overexpression was associated with poorer patient prognosis. Pharmacological inhibition of SHMT activity significantly reduced RCC cell proliferation and was accompanied by activation of the autophagic pathway. Furthermore, SHMT inhibition increased reactive oxygen species (ROS) production and markedly decreased mitochondrial spare respiratory capacity in ACHN cells. Notably, pharmacological inhibition of SHMTs sensitized RCC cell lines to the tyrosine kinase inhibitor sorafenib. Collectively, these findings highlight the role of SHMT2 in RCC metabolism and cell survival and suggest that pharmacological inhibition of SHMTs may represent a potential therapeutic strategy for RCC. Moreover, targeting SHMT activity may offer a promising approach to sensitize RCC to the TKIs and therefore, improving the efficacy of targeted therapies.