摘要
背景：吉非替尼是一种众所周知的针对包含EGFR突变的非小细胞肺癌（NSCLC）的酪氨酸激酶抑制剂。但是，其在治疗无此类EGFR突变的粘液表皮样癌（MEC）中的有效性提示了其他目标。 目的：已提出MEC典型的CRTC1-MAML2（C1-M2）融合蛋白是吉非替尼的靶标。 方法：为了验证该假设，我们开发了一组下调C1-M2表达的siRNA。应用RNA-seq和Western blot技术分析吉非替尼和siC1-M2对MEC细胞株H292中酪氨酸激酶的转录组和磷酸化的影响。 结果：深度测序转录组分析显示，吉非替尼广泛抑制JAK-STAT和MAPK / ERK途径中基因的转录。 siC1-M2和吉非替尼均抑制了这些信号通路中多种信号激酶的磷酸化，表明吉非替尼抑制了由C1-M2融合激活的JAK-STAT和MAPK / ERK通路。此外，吉非替尼对EGFR和MAPK / ERK的抑制作用比AKT，JAK2和STATs更有效，并且它们对C1-M2的依赖性可以解除。两者合计，我们的结果表明，吉非替尼同时抑制多种在MEC中激活的关键信号蛋白的磷酸化，部分是通过C1-M2融合。吉非替尼抑制的激酶磷酸化解释了JAK-STAT和MAPK / ERK途径中基因的转录抑制。 结论：这些发现为吉非替尼治疗粘液表皮样癌的疗效提供了新的见解，并建议将吉非替尼与其他专门针对C1-M2融合的抑制剂联合使用可能更有效。
关键词: 吉非替尼，CRTC1-MAML2融合蛋白，EGFR，JAK-STAT，粘液表皮样癌细胞，磷酸化。
图形摘要
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