KIT kinase mutants show unique mechanisms of drug resistance to imatinib and sunitinib in gastrointestinal stromal tumor patients
KIT kinase mutants show unique mechanisms of drug resistance to imatinib and sunitinib in gastrointestinal stromal tumor patients
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DOI：
10.1073/pnas.0812413106
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发表时间：
2009-02-03
影响因子：
11.1
通讯作者：
Demetri, George D.
中科院分区：
文献类型：
--
作者：
Gajiwala, Ketan S.;Wu, Joe C.;Demetri, George D.
大多数胃肠道间质瘤（gist）表现出受体酪氨酸激酶（RTK） KIT的异常激活。甲磺酸伊马替尼和苹果酸舒尼替尼抑制剂在GIST患者中的疗效与它们对这些突变KIT蛋白的抑制有关。然而，服用伊马替尼的患者可能获得继发性KIT突变，使蛋白质对抑制剂不敏感。舒尼替尼已经显示出对某些伊马替尼耐药突变体的有效性，尽管存在于激活环中的一个子集，包括D816H/V，仍然具有耐药性。进行了生化和结构研究以确定舒尼替尼耐药的分子基础。我们的研究结果表明，舒尼替尼靶向WT KIT的自抑制构象，并且D816H突变体经历了构象平衡向活性状态的转变。这些发现为KIT抑制剂的耐药谱提供了结构和酶学上的解释。展望未来，它们对理解致癌激酶突变体和规避耐药性具有重要意义。
Most gastrointestinal stromal tumors (GISTs) exhibit aberrant activation of the receptor tyrosine kinase (RTK) KIT. The efficacy of the inhibitors imatinib mesylate and sunitinib malate in GIST patients has been linked to their inhibition of these mutant KIT proteins. However, patients on imatinib can acquire secondary KIT mutations that render the protein insensitive to the inhibitor. Sunitinib has shown efficacy against certain imatinib-resistant mutants, although a subset that resides in the activation loop, including D816H/V, remains resistant. Biochemical and structural studies were undertaken to determine the molecular basis of sunitinib resistance. Our results show that sunitinib targets the autoinhibited conformation of WT KIT and that the D816H mutant undergoes a shift in conformational equilibrium toward the active state. These findings provide a structural and enzymologic explanation for the resistance profile observed with the KIT inhibitors. Prospectively, they have implications for understanding oncogenic kinase mutants and for circumventing drug resistance.