Synergistic effect of pacritinib with erlotinib on JAK2-mediated resistance in epidermal gowth factor receptor mutation-positive non-small cell lung Cancer.
Synergistic effect of pacritinib with erlotinib on JAK2-mediated resistance in epidermal gowth factor receptor mutation-positive non-small cell lung Cancer.
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pacritinib 与厄洛替尼对表皮生长因子受体突变阳性非小细胞肺癌中 JAK2 介导的耐药性的协同作用。
DOI：
10.1016/j.yexcr.2016.05.008
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Takigawa N.
中科院分区：
文献类型：
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作者：
Ochi N;Isozaki H;Takeyama M;Singer JW;Yamane H;Honda Y;Kiura K;Takigawa N.
研究了新型JAK 2/FLT 3抑制剂pacritinib与表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）厄洛替尼对EGFR激活突变的非小细胞肺癌细胞的联合作用。在某些情况下，该组合对JAK 2介导的EGFR TKI耐药PC-9/ER 3细胞显示出协同作用。该组合显著抑制pAKT和pERK，尽管在PC-9/ER 3细胞中，无论用pacritinib、pacritinib +厄洛替尼或对照处理，pSTAT 3表达相似。受体酪氨酸激酶阵列分析表明，pacritinib抑制MET在PC-9/ER 3细胞。在PC-9/ER 3异种移植物中，与单独使用每种药物相比，pacritinib和厄洛替尼的联合治疗显示出更多的肿瘤缩小。Western blotting显示肿瘤样品中的pMET被抑制。这些结果表明，pacritinib对MET的抑制可能在克服PC-9/ER 3细胞中JAK 2介导的EGFR-TKI耐药性方面发挥作用。综上所述，pacritinib联合EGFR-TKI可能是一种有效的抗JAK 2介导的EGFR-TKI耐药策略。
The combination effect of pacritinib, a novel JAK2/FLT3 inhibitor, with erlotinib, the epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), on non-small cell lung cancer cells with EGFR activating mutations was investigated. The combination showed synergistic effects on JAK2-mediated EGFR TKI-resistant PC-9/ER3 cells in some cases. The combination markedly suppressed pAKT and pERK although pSTAT3 expression was similar regardless of treatment with the pacritinib, pacritinib + erlotinib, or control in PC-9/ER3 cells. Receptor tyrosine kinase array profiling demonstrated that pacritinib suppressed MET in the PC-9/ER3 cells. The combined treatment of pacritinib and erlotinib in PC-9/ER3 xenografts showed more tumor shrinkage compared with each drug as monotherapy. Western blotting revealed that pMET in tumor samples was inhibited. These results suggest MET suppression by pacritinib may play a role in overcoming the EGFR-TKI resistance mediated by JAK2 in the PC-9/ER3 cells. In conclusion, pacritinib combined with EGFR-TKI might be a potent strategy against JAK2-mediated EGFR-TKI resistance.