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Accession IconGSE57422

Quinacrine Overcomes Resistance to Erlotinib by Inhibiting FACT, Nuclear Factor-kappa B and Cell Cycle Progression in Non-Small Cell Lung Cancer

Organism Icon Homo sapiens
Sample Icon 24 Downloadable Samples
Technology Badge Icon Affymetrix Human Gene 2.1 ST Array (hugene21st)

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Description
Erlotinib is a tyrosine kinase inhibitor (TKI) that is approved as a second-line monotherapy in patients with advanced non-small cell lung cancer (NSCLC). In these patients, erlotinib prolongs survival but its benefit remains modest since many tumors express wild-type EGF receptor (wtEGFR) lacking a TKI-sensitizing mutation, develop a second-site EGFR mutation, e.g., EGFR-L858R/T790M, or activate an alternate receptor tyrosine kinase, e.g., through MET amplification. To test potential drug combinations that could improve the efficacy of erlotinib, we combined erlotinib with quinacrine, which inhibits the FACT (facilitates chromatin transcription) complex that is required for nuclear factor-B (NF-B) transcriptional activity. In A549 (wtEGFR), H1975 (EGFR-L858R/T790M) and H1993 (MET amplification) NSCLC cells, the combination of erlotinib and quinacrine was highly synergistic, as quantified by Chou-Talalay combination indices. The combination inhibited colony formation, induced cell cycle arrest and apoptosis, and slowed xenograft tumor growth. Quinacrine decreased the level of active FACT subunit SSRP1 and suppressed NF-B-dependent luciferase activity. Knockdown of SSRP1 decreased cell growth and sensitized cells to erlotinib.
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