Crizotinib sensitizes the erlotinib resistant HCC827GR5 cell line by influencing lysosomal function. Issue 11 (20th January 2020)

• Record Type: Journal Article
• Authors: Van Der Steen, Nele; Keller, Kaylee; Dekker, Henk; Porcelli, Letizia; Honeywell, Richard J.; Van Meerloo, Johan; Musters, René J. P.; Kathmann, Ietje; Frampton, Adam E.; Liu, Daniel S. K.; Ruijtenbeek, Rob; Rolfo, Christian; Pauwels, Patrick; Giovannetti, Elisa; Peters, Godefridus J.
• Is Part Of: Journal of cellular physiology. Volume 235:Issue 11(2020:Nov.)
• Page Start: 8085
• Page End: 8097
• Publication Date: 2020-01-20
• Subjects: cMET -- crizotinib -- EGFR -- erlotinib -- lysosomes -- tyrosine kinase inhibitors; Physiology -- Periodicals; Cell physiology -- Periodicals; 571.6
• DOI: 10.1002/jcp.29463
• Languages: English
• ISSNs: 0021-9541

Abstract

Abstract: In non‐small cell lung cancer, sensitizing mutations in epidermal growth factor receptor (EGFR) or cMET amplification serve as good biomarkers for targeted therapies against EGFR or cMET, respectively. Here we aimed to determine how this different genetic background would affect the interaction between the EGFR‐inhibitor erlotinib and the cMET‐inhibitor crizotinib. To unravel the mechanism of synergy we investigated the effect of the drugs on various parameters, including cell cycle arrest, migration, protein phosphorylation, kinase activity, the expression of drug efflux pumps, intracellular drug concentrations, and live‐cell microscopy. We observed additive effects in EBC‐1, H1975, and HCC827, and a strong synergism in the HCC827GR5 cell line. This cell line is a clone of the HCC827 cells that harbor an EGFR exon 19 deletion and has been made resistant to the EGFR‐inhibitor gefitinib, resulting in cMET amplification. Remarkably, the intracellular concentration of crizotinib was significantly higher in HCC827GR5 compared to the parental HCC827 cell line. Furthermore, live‐cell microscopy with a pH‐sensitive probe showed a differential reaction of the pH in the cytoplasm and the lysosomes after drug treatment in the HCC827GR5 in comparison with the HCC827 cells. This change in pH could influence the process of lysosomal sequestration of drugs. These results led us to the conclusion that lysosomal sequestration is involved in the strong synergistic reaction of the HCC827GR5 cell line to crizotinib–erlotinib combination. This finding warrants future clinical studies to evaluate whether genetic background and lysosomal sequestration could guide tailored therapeutic interventions. Abstract : In non‐small cell lung cancer, sensitizing mutations in epidermal growth factor receptor (EGFR) or cMET amplification serve as good biomarkers for targeted therapies against EGFR or cMET, respectively. Here we aimed to determine how this different genetic background would affect the interaction between the EGFR‐inhibitor erlotinib and the cMET‐inhibitor crizotinib. Both genetic characteristics and lysosomal function seem to contribute to the synergistic interaction between crizotinib and erlotinib in the HCC827GR5 cell line, and more research is warranted to determine the exact mechanisms linking these cellular properties.