The adaptive activation of alternative signaling pathways contributes to acquired resistance against targeted cancer therapies. Our previous research has shown that blocking Ras/ERK signaling promotes PI3K/AKT signaling in the lung metastatic derivative of MDA-MB-231 (LM2). Because AKT activation was required to drive sustained cell motility following MEK suppression, we extend our research to elucidate how activation of the PI3K/AKT signaling drives sustained motility following MEK inhibition. Reverse phase protein array (RPPA) revealed that SNAIL (SNAI1) was upregulated in U0126 (MEK inhibitor)-treated LM2 cells. Importantly, LM2 cells simultaneously treated with U0126 and PI3K inhibitor LY294002 exhibited reduced expression of SNAIL. Furthermore, depletion of SNAIL led to reduced cell motility in U0126-treated LM2 cells. In addition, we identified AXL as another downstream effector of AKT. These results suggest that SNAIL and AXL are key factors mediating sustained motility of LM2 cells following MEK suppression. Because AKT mediates motile behavior under MEK suppression, our results suggest that AKT and AXL may be targeted to overcome resistance against drugs targeting the Ras/ERK pathway.

替代信号通路的适应性激活有助于获得针对靶向癌症治疗的耐药性。我们之前的研究表明，阻断 Ras/ERK 信号可促进 MDA-MB-231 (LM2) 肺转移衍生物中的 PI3K/AKT 信号。因为在 MEK 抑制后需要 AKT 激活来驱动持续的细胞运动，我们扩展了我们的研究以阐明 PI3K/AKT 信号的激活如何在 MEK 抑制后驱动持续的运动。反相蛋白阵列 (RPPA) 显示 SNAIL ( SNAI1 ) 在 U0126（MEK 抑制剂）处理的 LM2 细胞中上调。重要的是，同时用 U0126 和 PI3K 抑制剂 LY294002 处理的 LM2 细胞表现出 SNAIL 的表达降低。此外，SNAIL的消耗导致 U0126 处理的 LM2 细胞的细胞运动性降低。此外，我们将 AXL 确定为 AKT 的另一个下游效应器。这些结果表明，SNAIL 和 AXL 是介导 MEK 抑制后 LM2 细胞持续运动的关键因素。因为 AKT 在 MEK 抑制下介导运动行为，我们的结果表明 AKT 和 AXL 可能被靶向以克服对靶向 Ras/ERK 通路的药物的耐药性。