Targeting c-FOS and DUSP1 abrogates intrinsic resistance to tyrosine-kinase inhibitor therapy in BCR-ABL-induced leukemia.
Targeting c-FOS and DUSP1 abrogates intrinsic resistance to tyrosine-kinase inhibitor therapy in BCR-ABL-induced leukemia.
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DOI：
10.1038/nm.4310
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发表时间：
2017-04
期刊：
影响因子：
82.9
通讯作者：
Azam M
中科院分区：
文献类型：
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作者：
Kesarwani M;Kincaid Z;Gomaa A;Huber E;Rohrabaugh S;Siddiqui Z;Bouso MF;Latif T;Xu M;Komurov K;Mulloy JC;Cancelas JA;Grimes HL;Azam M
酪氨酸激酶抑制剂（TKI）治疗人类癌症并不能治愈，由于肿瘤细胞（称为微小残留病（MRD）细胞）的持续存在，癌症会复发。 MRD 干细胞或祖细胞在缺乏致癌激酶信号传导（一种称为内在抵抗的现象）的情况下存活取决于多种生长因子。在这里，我们报告致癌激酶和生长因子信号传导汇聚诱导信号蛋白 c-Fos 和 Dusp1 的表达。在 BCR-ABL 诱导的慢性粒细胞白血病 (CML) 小鼠模型中，c-Fos 和 Dusp1 的基因缺失可抑制肿瘤生长。 c-Fos、Dusp1 和 BCR-ABL 的药理学抑制在多种体内模型以及原发性 CML 患者异种移植小鼠中消除了 MRD。生长因子信号传导还赋予 TKI 耐药性，并在模拟其他类型激酶驱动的白血病的肿瘤细胞中诱导 c-FOS 和 DUSP1 表达。我们的数据表明，c-Fos 和 Dusp1 表达水平决定了 TKI 疗效的阈值，因此生长因子诱导的 c-Fos 和 Dusp1 表达在多种白血病中赋予了 TKI 治疗的内在抵抗力，并且可能代表了激酶驱动的癌症的统一致命弱点。
Tyrosine kinase inhibitor (TKI) therapy for human cancers is not curative, with relapse due to the continuing presence of tumor cells, referred to as minimal residual disease (MRD) cells. MRD stem or progenitor cells survival in the absence of oncogenic kinase signaling, a phenomenon referred to as intrinsic resistance, depends on diverse growth factors. Here, we report that oncogenic kinase and growth factor signaling converge to induce the expression of the signaling proteins c-Fos and Dusp1. Genetic deletion of c-Fos and Dusp1 suppressed tumor growth in a BCR-ABL-induced mouse model of chronic myeloid leukemia (CML). Pharmacological inhibition of c-Fos, Dusp1 and BCR-ABL eradicated MRD in multiple in vivo models, as well as in primary CML patient xenotransplanted mice. Growth factor signaling also conferred TKI resistance and induced c-FOS and DUSP1 expression in tumor cells modeling other types of kinase-driven leukemias. Our data demonstrate that c-Fos and Dusp1 expression levels determine the threshold of TKI efficacy, such that growth factor-induced expression of c-Fos and Dusp1 confers intrinsic resistance to TKI therapy in a wide-ranging set of leukemias, and may represent a unifying Achilles heel of kinase-driven cancers.