Folate receptor and transporter system (FR/RFC/PCFT)

Folate transporters and receptors are a specialized group of membrane proteins that mediate the cellular uptake of folates, which are critical cofactors for one-carbon metabolism, DNA synthesis, and cell division (Zhao & Goldman, 2013). This system includes the Folate Receptors (FR-alpha, FR-beta, and FR-gamma), the Reduced Folate Carrier (RFC/SLC19A1), and the Proton-Coupled Folate Transporter (PCFT/SLC46A1) (Hou & Matherly, 2014). FR-alpha (FOLR1) is of significant clinical interest because it is highly overexpressed in various epithelial cancers, such as ovarian, lung, and breast cancers, while maintaining restricted expression in healthy tissues (Cheung et al., 2016). In contrast, RFC is the primary transporter for folates in normal systemic circulation, and PCFT is essential for dietary folate absorption in the small intestine (Matherly et al., 2007). Pharmaceutical interventions exploit these pathways through two main strategies: the delivery of cytotoxic antifolates (like methotrexate and pemetrexed) via transporters, and the use of antibody-drug conjugates (ADCs) or ligand-targeted therapies that specifically bind to FR-alpha (Ledermann et al., 2015). Recent advancements, such as the FDA approval of mirvetuximab soravtansine, highlight the success of targeting FR-alpha in platinum-resistant ovarian cancer (Heo, 2023). Additionally, FR-beta is expressed on activated macrophages and is being explored as a target for inflammatory diseases like rheumatoid arthritis (Cheung et al., 2016). Safety concerns often involve off-target effects in tissues with low-level expression, such as the lungs or kidneys, or toxicities related to the cytotoxic payload of ADCs (Heo, 2023).

Other names

Folate receptorReduced folate carrierProton-coupled folate transporterFOLR1FOLR2SLC19A1SLC46A1Folate binding proteinFBPReduced folate carrier 1

Drugs targeting this system function either as substrates for transport into the cell (antifolates) or as targeted ligands/antibodies that bind to overexpressed receptors to deliver cytotoxic payloads or induce immune-mediated cell death (Cheung et al., 2016; Ledermann et al., 2015).