Compound 15c, a Novel Dual Inhibitor of EGFRL858R/T790M and FGFR1, Efficiently Overcomes Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor Resistance of Non-Small-Cell Lung Cancers
Compound 15c, a Novel Dual Inhibitor of EGFRL858R/T790M and FGFR1, Efficiently Overcomes Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor Resistance of Non-Small-Cell Lung Cancers
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DOI：
10.3389/fphar.2019.01533
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发表时间：
2020-01-10
影响因子：
5.6
通讯作者：
Liang, Guang
中科院分区：
文献类型：
--
作者：
Chen, Gaozhi;Bao, Yuyan;Liang, Guang
表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）是治疗EGFR突变型非小细胞肺癌（NSCLC）的有效药物。然而，EGFR-TKI的耐受性总是在连续给药一段时间后发生，限制了这些药物的应用。FGFR 1信号通路的激活是NSCLC耐EGFR-TKI的重要逃逸机制之一。在此，发现了一种新的EGFR（L 858 R/T790 M）和FGFR 1的双重抑制剂，化合物15 c，并且可以通过其同时抑制它们的激酶活性而有效地克服EGFR-TKI抗性。与EGFR（L 858 R/T790 M）和FGFR 1抑制剂单独或联合治疗的比较显示，15 c对EGFR（L 858 R/T790 M）和FGFR 1活性的抑制是克服EGFR（L 858 R/T790 M）突变H1975细胞中固有EGFR-TKI耐药性和阿法替尼耐受PC 9细胞（AFA-PC 9）中获得性耐药性的原因。流式细胞术和Caspase 3活性分析显示15 c可诱导H1975细胞早期凋亡。BALB/c小鼠中由H1975细胞诱导的异种移植瘤形成被15 c处理抑制，动物体重没有变化。通常，15 c可作为新一代EGFR-TKI用于治疗对当前TKI耐药的NSCLC患者。
In the past decades, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) had been proved as an effective treatment strategy for the patients with EGFR-mutated non-small-cell lung cancer (NSCLC). However, the tolerance for the EGFR-TKI always occurred after continuous administration for a period of time and limiting the application of these drugs. Activation of FGFR1 signaling pathway was one of the important escape mechanisms for EGFR-TKI resistant in NSCLC. Here, a novel dual inhibitor of EGFR(L858R/T790M) and FGFR1, compound15c, was found and can efficiently overcame the EGFR-TKI resistance via its simultaneous inhibition of their kinase activities. Comparison with EGFR(L858R/T790M) and FGFR1 inhibitor treatment alone or combined revealed that the inhibition of EGFR(L858R/T790M) and FGFR1 activity by 15c was responsible for surmounting the intrinsic EGFR-TKI resistance in EGFR(L858R/T790M)-mutated H1975 cells and the acquired resistance in Afatinib-tolerant PC9 cells (AFA-PC9). Flow Cytometry and Caspase3 activity analysis assay showed that 15c induced significant the early apoptosis of H1975 cells. Xenograft tumor formation in BALB/c mice induced by a H1975 cells was suppressed by 15c treatment, with no changes in animal body weight. Generally, 15c may act as a new-generation EGFR-TKI for the therapy of NSCLC patients suffering a resistance to current TKI.