III. Medizinische Universitätsklinik, Universitätsmedizin Mannheim der Universität Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.
J Cancer Res Clin Oncol. 2012 Feb;138(2):203-12. doi: 10.1007/s00432-011-1086-x. Epub 2011 Nov 17.
Targeted treatment of chronic myelogenous leukemia using imatinib has dramatically improved patient outcome. However, residual disease can be detected in the majority of patients treated with imatinib. Compensatory activation of MAP kinases (MAPK1/2) in response to BCR-ABL-inhibitors has been reported as a potential cytokine-dependent resistance mechanism leading to the rescue of leukemic progenitor cells.
Differential MAPK-modulating activity of clinically approved tyrosine kinase inhibitors was assessed in vitro using BCR-ABL-transformed cells. CD34+-enriched progenitors of newly diagnosed chronic myelogenous leukemia patients were exposed to tyrosine kinase inhibitors. MAPK-signaling was studied by Western blot technique. Proliferation assays were used to analyze response to antileukemic treatment.
The ABL-inhibitors imatinib and nilotinib activate MAPKs in CD34+ chronic myelogenous leukemia progenitor cells, whereas treatment with the SRC/ABL-inhibitor dasatinib does not affect MAPK-activation at clinically relevant concentrations. Similar results are seen in BCR-ABL-transformed cells in the presence of interleukin-3 (IL-3). Experiments using BCR-ABL-mutant T315I, a resistance mutation not amenable to tyrosine kinase inhibitor binding, demonstrate that ABL-inhibitor-induced MAPK-activation does not depend on BCR-ABL-inhibition and cannot be prevented by selective SRC-inhibition. However, BCR-ABL-T315I enhances MAPK-activation, suggesting a T315I-dependent positive feedback of MAPK-activation. An autocrine IL-3-loop as trigger for aberrant T315I-dependent MAPK-activation was excluded.
Aberrant MAPK-activation triggered by ABL-inhibitors and positively regulated by BCR-ABL kinase mutation T315I might be an experimental explanation for the clinical observation that patients carrying high-resistance mutations show a highly aggressive course of their disease when tyrosine kinase inhibitor treatment is not discontinued in time.
使用伊马替尼靶向治疗慢性髓性白血病显著改善了患者的预后。然而，接受伊马替尼治疗的大多数患者仍可检测到残留疾病。已有报道称，BCR-ABL 抑制剂作用下 MAP 激酶（MAPK1/2）的代偿性激活是导致白血病祖细胞耐药的潜在细胞因子依赖性机制之一。
采用 Western blot 技术检测临床批准的酪氨酸激酶抑制剂在体外对 BCR-ABL 转化细胞的差异 MAPK 调节活性。将新诊断的慢性髓性白血病患者的 CD34+祖细胞暴露于酪氨酸激酶抑制剂中。用增殖实验分析抗白血病治疗的反应。
ABL 抑制剂伊马替尼和尼罗替尼可激活 CD34+慢性髓性白血病祖细胞中的 MAPK，而临床相关浓度下 SRC/ABL 抑制剂达沙替尼治疗则不影响 MAPK 激活。在白细胞介素 3（IL-3）存在的情况下，BCR-ABL 转化细胞中也观察到类似的结果。使用 BCR-ABL 突变 T315I（一种不能与酪氨酸激酶抑制剂结合的耐药突变）的实验表明，ABL 抑制剂诱导的 MAPK 激活不依赖于 BCR-ABL 抑制，也不能通过选择性 SRC 抑制来预防。然而，BCR-ABL-T315I 增强了 MAPK 激活，表明 MAPK 激活存在 T315I 依赖性正反馈。排除了作为异常 T315I 依赖性 MAPK 激活触发因素的自分泌 IL-3 环。
ABL 抑制剂触发的异常 MAPK 激活以及 BCR-ABL 激酶突变 T315I 的正调节可能是一个实验性解释，说明携带高耐药突变的患者在未及时停止酪氨酸激酶抑制剂治疗时，其疾病进展具有高度侵袭性。
