抑制AXL，延缓her2和egfr的靶向药耐药
一、AXL表达升高，是her2靶向药耐药的主要原因之一1、“ Genetic depletion and pharmacological inhibition of AXL restored trastuzumab response in vitro and in vivo. AXL inhibitor plus trastuzumab achieved complete regression in trastuzumab-resistant patient-derived xenograft models.” （《Targeting HER2-AXL heterodimerization to overcome resistance to HER2 blockade in breast cancer》）
2、“We show overexpression of AXL as a novel mechanism of acquired resistance to HER2-targeted agents in these models.” （《Novel mechanism of lapatinib resistance in HER2-positive breast tumor cells: activation of AXL》）
二、AXL表达升高，是EGFR靶向药耐药的主要原因之一
1、“AXL was highly expressed in clinical specimens of EGFR-mutated lung cancers and its high expression was associated with a low response rate to EGFR-TKI.” （《AXL confers intrinsic resistance to osimertinib and advances the emergence of tolerant cells》）
2、“Here, we report increased activation of AXL and evidence for epithelial-to-mesenchymal transition (EMT) in multiple in vitro and in vivo EGFR-mutant lung cancer models with acquired resistance to erlotinib in the absence of the EGFR p.Thr790Met alteration or MET activation.” （《Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer》）
3、“our results identify AXL as a key mediator of cetuximab resistance” （《AXL mediates resistance to cetuximab therapy》）
三、抑制AXL的药物
1、目前还没有AXL单一靶点的靶向药上市。AXL与MET会形成异二聚体，所以一些常用作MET靶向药的多靶点药物，往往有AXL的靶点，例如：
“ Merestinib (LY2801653) 是一种2型ATP竞争型的慢抑制剂，抑制Met (c-Met)酪氨酸激酶，Ki值为2 nM。药效的停留时间为0.00132 min(-1)，t1/2为525 min。Merestinib (LY2801653) 还可抑制MST1R、AXL、ROS1、MKNK1/2、FLT3、MERTK、DDR1和DDR2，其对应的IC50值分别为11 nM、2 nM、23 nM、7 nM、7 nM、10 nM、0.1 nM 和 7 nM。”
“Cabozantinib (XL184, BMS-907351)是一种有效的VEGFR2抑制剂，在无细胞试验中IC50为0.035 nM，也能有效抑制c-Met、 Ret、 Kit、Flt-1/3/4、Tie2和AXL，IC50分别为1.3 nM，4 nM，4.6 nM，12 nM/11.3 nM/6 nM，14.3 nM 和 7 nM。”
2、有能抑制AXL的替代药物。
（1）吗丁啉、昂丹司琼
“The Domperidone drug molecule is showing a very good in vitro inhibition value become an attracted molecule for drug repurposing for breast cancer. The best QSAR from a 37 training set molecules generated with R2 of 0.91 and Q2 of 0.86. ” （《In silico screening of FDA approved drugs on AXL kinase and validation for breast cancer cell line》）
（2）青蒿琥酯
“可见青蒿琥酯作用48 h后PC9 细胞内Axl、Akt、p - Axl、p - Akt蛋白的表达较对照组均有不同程度的降低, 且以p - Axl和p- Akt降低更为明显 ( 见图4) 。” （《青蒿琥酯对肺腺癌PC9细胞中Axl及其下游信号分子的影响》）
（3）双氢青蒿素
“DHA reversed the osimertinib-induced STAT3 and Src phosphorylation. The double combination inhibited AXL expression.” （《Osimertinib and dihydroartemisinin: a novel drug combination targeting head and neck squamous cell carcinoma》）
没有明确的AXL突变只是野生型高表达的时候，从用药的整体规划角度，没必要用那些met的靶向药，尤其是2型的。因为met扩增、突变本来就是her2和egfr靶向药的主要的获得性耐药突变之一，met的靶向药抢先用了，后续用药会有问题。
可以先用那些替代药物，毕竟奥西替尼+双氢青蒿素的“The double combination”也能 “inhibited AXL expression.”
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