印度代购提示您，劳拉替尼作为目前ALK靶向领域最后的“保底”药物，能克服多种ALK靶向药耐药，但它最终也面临耐药。例如，溶剂前沿突变G1202R+L1196M，几乎来者不拒，对任何现有ALK-TKI耐药。研究新一代的靶向药永远在路上。近期，科学家发现，一款用于急性髓系白血病的药物具有很好的应用潜力，这就是吉列替尼(Gilteritinib)。吉列替尼是一种有效的、选择性FLT3口服抑制剂，靶向FTL3与Axl，获批用于携带FLT3突变的复发或难治性急性髓系白血病成人患者。

India daigou reminds you that loratinib, as the last "guarantee" drug in the current ALK-targeting field, can overcome a variety of ALK-targeting drug resistance, but it will eventually face drug resistance. For example, the solvent frontier mutation G1202R+L1196M, almost universally accepted, is resistant to any existing ALK-TKI. Research on a new generation of targeted drugs is always on the way. Gilteritinib has been identified as a potential drug for acute myeloid leukemia. Giletinib is an effective, selective oral FLT3 inhibitor that targets FTL3 and Axl and is approved for use in adults with relapsed or refractory acute myeloid leukemia carrying FLT3 mutations.

　　印度代购提示您，吉列替尼能克服ALK通路的难治耐药突变。EML4-ALK I1171N+F1174I和I1171N+L1198H这两个复合突变对目前所有获批的ALK-TKI都耐药，因此科学家扩大搜寻范围，在更多靶向药中寻找答案。大量实验后，他们发现吉列替尼能很好的杀伤存在这两种突变的肿瘤细胞。这也是他们最初将视线定格在吉列替尼上的原因。

　　印度代购提示您，经过严谨的实验验证，科学家证实该药作用于NSCLC的ALK通路。那对前代ALK-TKI的耐药突变是否有作用呢?惊奇的是，吉列替尼在较低药物浓度时即对一二代ALK-TKI耐药突变具有很好的抑制效果;体内实验中，对阿来替尼耐药I1171N突变产生的小鼠皮下移植瘤，治疗3个月左右时肿瘤几乎消失(图2b)。低浓度、高抑制的数据，提示吉列替尼或能在较小不良事件的前提下达到逆转一二代ALK-TKI耐药的效果。

　　印度代购提示您，那对“皇冠级”的劳拉替尼耐药后效果如何?令人欣慰的是，对劳拉替尼治疗后出现的多种耐药，吉列替尼在较低浓度下均有抑制效果。此外，对存在ALK I1171N+F1174I复合突变的小鼠皮下移植瘤，经过阿来替尼或劳拉替尼治疗后耐药时采用吉列替尼可以成功逆转;而一直使用吉列替尼治疗的小鼠肿瘤体积一直未见增大，完全缓解持续已达50天。这些结果表明，吉列替尼能“搞定”劳拉替尼耐药;对劳拉替尼治疗常见的I1171N+F1174I复合难治性耐药突变，吉列替尼可起到逆转效果。

　　印度代购提示您，此外，对采用多种ALK-TKI治疗后出现的G1202R+L1196M，D1203N+F1245V等复合突变，吉列替尼也都有一定的抑制作用。

　　印度代购提示您，吉列替尼对溶剂前沿突变的抑制效果(细胞活力-药物浓度曲线)(a)吉列替尼针对不同突变(Ba/F3);(b)吉列替尼及多种TKI(MR347)

　　印度代购提示您，吉列替尼能克服旁路激活耐药机制。旁路激活是ALK-TKI耐药的另一大原因，常见的有AXL，KRAS，EGFR突变等。研究者对吉列替尼对这些机制的治疗效果进行探索.对AXL突变，吉列替尼具有很好的控制效果;对接受二代TKI阿来替尼治疗后出现体积增大的肿瘤，换用吉列替尼具有逆转效果。对KRASG12C突变，吉列替尼具有部分肿瘤控制效果，而当其与KRAS靶向药AMG510联合应用时，控制效果最佳。对EGFR通路突变，吉列替尼单药的控制效果似乎不佳;而与二代EGFR-TKI阿法替尼联合使用时，具有一定控制效果。这些数据表明，吉列替尼单药或联合其他靶向药的使用策略，对常见的旁路耐药途径具有很好的抑制作用。

India daigou suggests that giletinib can overcome the mechanism of bypass activation of drug resistance. Bypass activation is another major cause of ALK-TKI resistance, and AXL, KRAS, EGFR mutations are common. The researchers explored the therapeutic effects of giletinib on these mechanisms. Giletinib has a good control effect on AXL mutation. Switching to giletinib has a reverse effect on tumors that have increased in size after treatment with second-generation TKI aletinib. For KRASG12C mutations, giletinib had partial tumor control, which was best achieved when combined with KRAS-targeted drug AMG510. For EGFR pathway mutations, giletinib monotherapy appears to be ineffective; When combined with the second generation EGFR-TKI afatinib, it had a certain control effect. These data suggest that a strategy of giletinib alone or in combination with other targeted agents has a good inhibitory effect on common bypass drug resistance pathways.