Erlotinib, a tyrosine kinase inhibitor, is clinically approved for treating advanced non-small cell lung cancer (NSCLC). While it extends survival, its efficacy remains limited due to intrinsic or acquired resistance mechanisms, particularly in tumors with wild-type EGFR or secondary mutations such as T790M. To enhance erlotinib’s therapeutic potential, researchers explored combining it with quinacrine, a drug known to inhibit the FACT complex—a key regulator of chromatin transcription and NF-κB activity. The combination demonstrated strong synergistic effects across multiple NSCLC cell lines, including A549 (wild-type EGFR), H1975 (EGFR-L858R/T790M), and H1993 (MET amplified). Using the Chou-Talalay method, combination indices confirmed synergy at both 5:1 and 10:1 molar ratios of erlotinib to quinacrine. This synergy translated into significant inhibition of xenograft tumor growth in vivo.
At sub-IC50 concentrations of erlotinib—more reflective of achievable clinical levels—quinacrine alone or in combination significantly suppressed colony formation, induced G1/S and G2/M phase cell cycle arrest, and triggered apoptosis. Mechanistically, quinacrine reduced active SSRP1, a critical subunit of the FACT complex, and suppressed NF-κB-dependent luciferase reporter activity.1,4-bUtanedithiol Cancer Knockdown of SSRP1 mirrored these effects, reducing cell viability and sensitizing cells to erlotinib.Anti-LY6G6D Antibody Biological Activity Transcriptomic profiling revealed that the combination altered expression of cell cycle-related genes regulated by transcription factors linked to SSRP1 targets.PMID:34473330 Notably, genes more potently suppressed by the combination were associated with poor prognosis in lung adenocarcinoma patients, suggesting their utility as predictive biomarkers.
These findings demonstrate that quinacrine overcomes erlotinib resistance by simultaneously targeting FACT-mediated transcription, NF-κB signaling, and cell cycle progression. The results support ongoing clinical evaluation of this combination in advanced NSCLC, offering a promising strategy to improve outcomes in patients with limited treatment options.MedChemExpress (MCE) offers a wide range of high-quality research chemicals and biochemicals (novel life-science reagents, reference compounds and natural compounds) for scientific use. We have professionally experienced and friendly staff to meet your needs. We are a competent and trustworthy partner for your research and scientific projects.Related websites: https://www.medchemexpress.com