Product Description

Pemetrexed is an antifolate, inhibiting thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), respectively.Pemetrexed inhibits cell replication, thereby inhibiting tumor growth, and it can be used in combination with cisplatin to treat inoperable malignant pleural mesothelioma.

Screeningbio‘s K562/ Pemetrexed resistance cell line generated by exposing to increasing concentration of drug for certain period of time. After stable acquire resistance, cells were harvested and characterized for drug resistance by 7 days proliferation assay.

Data

Target Background

Pemetrexed (Alimta) is a multitargeted antifolate chemotherapeutic agent that inhibits key enzymes in folate-dependent metabolic pathways, including thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT). By disrupting purine and pyrimidine synthesis, pemetrexed leads to DNA replication arrest and apoptosis in rapidly dividing cancer cells. It is primarily used in the treatment of non‑squamous non‑small cell lung cancer (NSCLC) and malignant pleural mesothelioma. However, acquired resistance remains a major clinical obstacle limiting its long‑term efficacy.

Mechanistically, pemetrexed resistance arises through multiple cellular adaptations. Reduced expression or functional impairment of the reduced folate carrier (RFC/SLC19A1) and folate receptors decreases intracellular drug uptake, while upregulation of efflux transporters such as ABCG2 (BCRP) and ABCC1 (MRP1) enhances drug extrusion. Increased expression or mutation of the primary target thymidylate synthase (TS) reduces drug binding affinity and permits continued DNA synthesis. Activation of survival pathways—including PI3K/Akt and MAPK signaling—promotes anti‑apoptotic responses. Additionally, alterations in folate metabolism enzymes (e.g., folylpolyglutamate synthetase, FPGS) that reduce drug polyglutamation, as well as enhanced autophagy or epithelial–mesenchymal transition (EMT), also contribute to reduced drug sensitivity.

Understanding these mechanisms is critical for designing strategies to overcome resistance, such as combining pemetrexed with TS inhibitors, targeting ABC transporter activity, modulating folate homeostasis, or employing patient‑derived resistant cell models to guide personalized therapy development.