PKC412在FIP1L1-PDGFRα诱导的骨髓增殖性疾病小鼠模型中克服了对伊马替尼的耐药性。
PKC412 overcomes resistance to imatinib in a murine model of FIP1L1-PDGFRα-induced myeloproliferative disease.
作者信息
Cools Jan, Stover Elizabeth H, Boulton Christina L, Gotlib Jason, Legare Robert D, Amaral Sonia M, Curley David P, Duclos Nicole, Rowan Rebecca, Kutok Jeffery L, Lee Benjamin H, Williams Ifor R, Coutre Steven E, Stone Richard M, DeAngelo Daniel J, Marynen Peter, Manley Paul W, Meyer Thomas, Fabbro Doriano, Neuberg Donna, Weisberg Ellen, Griffin James D, Gilliland D Gary
机构信息
Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
出版信息
Cancer Cell. 2003 May;3(5):459-69. doi: 10.1016/s1535-6108(03)00108-9.
FIP1L1-PDGFRalpha causes hypereosinophilic syndrome (HES) and is inhibited by the tyrosine kinase inhibitor imatinib (Gleevec). Imatinib is a potent inhibitor of ABL, ARG, PDGFRalpha, PDGFRbeta, and KIT and induces durable hematologic responses in HES patients. However, we observed relapse with resistance to imatinib as consequence of a T674I mutation in FIP1L1-PDGFRalpha, analogous to the imatinib-resistant T315I mutation in BCR-ABL. We developed a murine bone marrow transplant model of FIP1L1-PDGFRalpha-induced myeloproliferative disease to evaluate the efficacy of PKC412, an alternative inhibitor of PDGFRalpha, for the treatment of HES. PKC412 is effective for treatment of FIP1L1-PDGFRalpha-induced disease and of imatinib-induced resistance due to the T674I mutation. Our data establish PKC412 as molecularly targeted therapy for HES and other diseases expressing activated PDGFRalpha and demonstrate the potential of alternative kinase inhibitors to overcome resistance in target tyrosine kinases.
FIP1L1-PDGFRα可导致嗜酸性粒细胞增多综合征（HES），并可被酪氨酸激酶抑制剂伊马替尼（格列卫）抑制。伊马替尼是ABL、ARG、PDGFRα、PDGFRβ和KIT的强效抑制剂，可在HES患者中诱导持久的血液学反应。然而，我们观察到FIP1L1-PDGFRα中T674I突变导致对伊马替尼产生耐药性并出现复发，这类似于BCR-ABL中对伊马替尼耐药的T315I突变。我们建立了FIP1L1-PDGFRα诱导的骨髓增殖性疾病的小鼠骨髓移植模型，以评估PDGFRα的另一种抑制剂PKC412治疗HES的疗效。PKC412对治疗FIP1L1-PDGFRα诱导的疾病以及由T674I突变引起的伊马替尼耐药有效。我们的数据确立了PKC412作为针对HES和其他表达活化PDGFRα的疾病的分子靶向治疗方法，并证明了替代激酶抑制剂克服靶酪氨酸激酶耐药性的潜力。
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