Activating JAK-mutations confer resistance to FLT3 kinase inhibitors in FLT3-ITD positive AML in vitro and in vivo
Activating JAK-mutations confer resistance to FLT3 kinase inhibitors in FLT3-ITD positive AML in vitro and in vivo
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DOI：
10.1038/s41375-020-01077-1
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发表时间：
2020-11-04
期刊：
影响因子：
11.4
通讯作者：
von Bubnoff, Nikolas
中科院分区：
文献类型：
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作者：
Rummelt, Christoph;Gorantla, Sivahari P.;von Bubnoff, Nikolas
Flt3酪氨酸激酶抑制剂(TKIs)治疗Flt3-ITD阳性AML的一个重要局限性是产生耐药性。为了更好地了解对Flt3抑制的耐药性，我们检测了对米多妥林或索拉非尼具有获得性耐药性的Flt3-ITD阳性细胞株。在23个TKI耐药细胞系中的6个中，我们能够检测到JAK1 V658F突变，该突变导致CSF2RB-STAT5途径重新激活。敲除JAK1或用JAK抑制剂处理可使细胞对Flt3抑制重新敏感。在136例突变AML并暴露于Flt3抑制剂的患者中，我们发现其中6例(4.4%)有7个不同的JAK家族突变，其中5个是真正的激活突变。除1例患者外，暴露于Flt3TKI后，JAK基因突变发生在新生(n=4)或变异等位基因频率增加(n=1)。在体外，5个激活变异体都可以诱导对Flt3-ITD抑制的抗性，然后通过对Flt3/JAK的双重抑制来克服这种抗性。总之，我们的数据描述了一种新的抵抗Flt3-ITD抑制的机制，并可能提供一种潜在的治疗方法，使用双重JAK和Flt3抑制。
An important limitation of FLT3 tyrosine kinase inhibitors (TKIs) in FLT3-ITD positive AML is the development of resistance. To better understand resistance to FLT3 inhibition, we examined FLT3-ITD positive cell lines which had acquired resistance to midostaurin or sorafenib. In 6 out of 23 TKI resistant cell lines we were able to detect a JAK1 V658F mutation, a mutation that led to reactivation of the CSF2RB-STAT5 pathway. Knockdown of JAK1, or treatment with a JAK inhibitor, resensitized cells to FLT3 inhibition. Out of 136 patients with FLT3-ITD mutated AML and exposed to FLT3 inhibitor, we found seven different JAK family mutations in six of the cases (4.4%), including five bona fide, activating mutations. Except for one patient, the JAK mutations occurred de novo (n = 4) or displayed increasing variant allele frequency after exposure to FLT3 TKI (n = 1). In vitro each of the five activating variants were found to induce resistance to FLT3-ITD inhibition, which was then overcome by dual FLT3/JAK inhibition. In conclusion, our data characterize a novel mechanism of resistance to FLT3-ITD inhibition and may offer a potential therapy, using dual JAK and FLT3 inhibition.