FOLR1 promotes sorafenib resistance by enhancing folic acid uptake to activate SRC/ERK signaling pathway in hepatocellular carcinoma

Sorafenib as a classic targeted therapeutic agent for advanced hepatocellular carcinoma (HCC) is still facing a severe challenge of drug resistance. Our previous studies showed that the up-regulation of autophagy by FOLR1 expression is the cause of drug resistance in HCC cells, but the detailed mechanism by which FOLR1 reduces the sensitivity of sorafenib remains unclear. In this study, we found that the ERK signaling pathway inhibited by sorafenib was reactivated in the FOLR1 overexpression HCC cells in the presence of folic acid. Mechanistically, the high expression of FOLR1 enhanced the ability of cells to uptake folic acid, which increased the binding ability of FOLR1 to SRC protein and SRC DNA promoter region to enhance the expression level of SRC kinase, leading to ERK signaling pathway activation originally inhibited by sorafenib in HCC cells, which provides a new therapeutic approach and therapeutic target and strategy for HCC patients.