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Crizotinib sensitizes the erlotinib resistant HCC827GR5 cell line by influencing lysosomal function.
Journal of Cellular Physiology ( IF 4.5 ) Pub Date : 2020-01-20 , DOI: 10.1002/jcp.29463 Nele Van Der Steen 1, 2, 3 , Kaylee Keller 3 , Henk Dekker 3 , Letizia Porcelli 4 , Richard J Honeywell 3 , Johan Van Meerloo 5 , René J P Musters 6 , Ietje Kathmann 3 , Adam E Frampton 7, 8 , Daniel S K Liu 7 , Rob Ruijtenbeek 9 , Christian Rolfo 1, 10 , Patrick Pauwels 1, 2 , Elisa Giovannetti 3, 11 , Godefridus J Peters 3
Journal of Cellular Physiology ( IF 4.5 ) Pub Date : 2020-01-20 , DOI: 10.1002/jcp.29463 Nele Van Der Steen 1, 2, 3 , Kaylee Keller 3 , Henk Dekker 3 , Letizia Porcelli 4 , Richard J Honeywell 3 , Johan Van Meerloo 5 , René J P Musters 6 , Ietje Kathmann 3 , Adam E Frampton 7, 8 , Daniel S K Liu 7 , Rob Ruijtenbeek 9 , Christian Rolfo 1, 10 , Patrick Pauwels 1, 2 , Elisa Giovannetti 3, 11 , Godefridus J Peters 3
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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.
中文翻译：
克唑替尼通过影响溶酶体功能来使耐埃洛替尼的HCC827GR5细胞系致敏。
在非小细胞肺癌中，表皮生长因子受体（EGFR）或cMET扩增的致敏突变分别作为针对EGFR或cMET的靶向治疗的良好生物标志物。在这里，我们旨在确定这种不同的遗传背景将如何影响EGFR抑制剂埃洛替尼和cMET抑制剂克唑替尼之间的相互作用。为了阐明协同作用的机制，我们研究了药物对各种参数的影响，包括细胞周期停滞，迁移，蛋白质磷酸化，激酶活性，药物外排泵的表达，细胞内药物浓度和活细胞显微镜检查。我们观察到了EBC-1，H1975和HCC827的加性效应，以及HCC827GR5细胞系的强协同作用。该细胞系是具有EGFR外显子19缺失的HCC827细胞的克隆，并已对EGFR抑制剂吉非替尼产生抗性，导致cMET扩增。值得注意的是，与亲本HCC827细胞系相比，HCC827GR5中克唑替尼的细胞内浓度明显更高。此外，用pH敏感探针进行的活细胞显微镜检查显示，与HCC827细胞相比，在HCC827GR5中进行药物处理后，细胞质和溶酶体的pH值存在差异。pH值的这种变化可能会影响药物溶酶体隔离的过程。这些结果使我们得出结论，溶酶体隔离与HCC827GR5细胞系对克唑替尼-厄洛替尼的强协同作用有关。
更新日期：2020-01-20
中文翻译：
克唑替尼通过影响溶酶体功能来使耐埃洛替尼的HCC827GR5细胞系致敏。
在非小细胞肺癌中，表皮生长因子受体（EGFR）或cMET扩增的致敏突变分别作为针对EGFR或cMET的靶向治疗的良好生物标志物。在这里，我们旨在确定这种不同的遗传背景将如何影响EGFR抑制剂埃洛替尼和cMET抑制剂克唑替尼之间的相互作用。为了阐明协同作用的机制，我们研究了药物对各种参数的影响，包括细胞周期停滞，迁移，蛋白质磷酸化，激酶活性，药物外排泵的表达，细胞内药物浓度和活细胞显微镜检查。我们观察到了EBC-1，H1975和HCC827的加性效应，以及HCC827GR5细胞系的强协同作用。该细胞系是具有EGFR外显子19缺失的HCC827细胞的克隆，并已对EGFR抑制剂吉非替尼产生抗性，导致cMET扩增。值得注意的是，与亲本HCC827细胞系相比，HCC827GR5中克唑替尼的细胞内浓度明显更高。此外，用pH敏感探针进行的活细胞显微镜检查显示，与HCC827细胞相比，在HCC827GR5中进行药物处理后，细胞质和溶酶体的pH值存在差异。pH值的这种变化可能会影响药物溶酶体隔离的过程。这些结果使我们得出结论，溶酶体隔离与HCC827GR5细胞系对克唑替尼-厄洛替尼的强协同作用有关。
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