Ponatinib overcomes FGF2-mediated resistance in CML patients without kinase domain mutations
Ponatinib overcomes FGF2-mediated resistance in CML patients without kinase domain mutations
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DOI：
10.1182/blood-2013-07-518381
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发表时间：
2014-03-06
期刊：
影响因子：
20.3
通讯作者：
Druker, Brian J.
中科院分区：
文献类型：
--
作者：
Traer, Elie;Javidi-Sharifi, Nathalie;Druker, Brian J.
对激酶抑制剂的耐药性的发展仍然是一个临床挑战。激酶结构域突变是慢性粒细胞白血病（CML）耐药的常见机制，但在缺乏突变的耐药机制仍不清楚。我们测试了骨髓微环境中的蛋白质，发现FGF 2在体外促进了对伊马替尼的耐药性。成纤维细胞生长因子2（FGF 2）是唯一能够通过FGF受体3/RAS/c-RAF/丝裂原活化蛋白激酶途径在短期和长期试验中促进生长的。泊那替尼是一种靶向BCR-ABL和FGF受体的多激酶抑制剂，可以克服耐药性。在临床上，我们确定了没有激酶结构域突变的CML患者，他们对多种ABL激酶抑制剂耐药，并对泊那替尼治疗有反应。与激酶结构域突变的CML患者相比，通过免疫组织化学分析，这些患者的骨髓中FGF 2增加。此外，骨髓中的FGF 2与对泊那替尼的反应同时降低，进一步表明FGF 2介导的抗性被FGF受体抑制中断。这些结果说明了配体诱导的激酶抑制剂耐药性的临床重要性，并支持开发合理的抑制剂组合来规避耐药性的方法。
Development of resistance to kinase inhibitors remains a clinical challenge. Kinase domain mutations are a common mechanism of resistance in chronic myeloid leukemia (CML), yet the mechanism of resistance in the absence of mutations remains unclear. We tested proteins from the bone marrow microenvironment and found that FGF2 promotes resistance to imatinib in vitro. Fibroblast growth factor 2 (FGF2) was uniquely capable of promoting growth in both short-and long-term assays through the FGF receptor 3/RAS/c-RAF/mitogen-activated protein kinase pathway. Resistance could be overcome with ponatinib, a multikinase inhibitor that targets BCR-ABL and FGF receptor. Clinically, we identified CML patients without kinase domain mutations who were resistant to multiple ABL kinase inhibitors and responded to ponatinib treatment. In comparison to CML patients with kinase domain mutations, these patients had increased FGF2 in their bone marrow when analyzed by immunohistochemistry. Moreover, FGF2 in the marrow decreased concurrently with response to ponatinib, further suggesting that FGF2-mediated resistance is interrupted by FGF receptor inhibition. These results illustrate the clinical importance of ligand-induced resistance to kinase inhibitors and support an approach of developing rational inhibitor combinations to circumvent resistance.