FMS-Like Tyrosine Kinase 3-Internal Tandem Duplication Tyrosine Kinase Inhibitors Display a Nonoverlapping Profile of Resistance Mutations In vitro
FMS-Like Tyrosine Kinase 3-Internal Tandem Duplication Tyrosine Kinase Inhibitors Display a Nonoverlapping Profile of Resistance Mutations In vitro
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DOI：
10.1158/0008-5472.can-08-2923
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发表时间：
2009-04-01
期刊：
影响因子：
11.2
通讯作者：
Duyster, Justus
中科院分区：
文献类型：
--
作者：
von Bubnoff, Nikolas;Engh, Richard A.;Duyster, Justus
FMS样酪氨酸激酶3（FLT 3）抑制剂在急性髓性白血病（AML）的治疗中显示出活性。靶激酶的继发性突变可导致对治疗性激酶抑制的临床耐药性。我们以前已经表明，对酪氨酸激酶抑制剂的敏感性在不同的激活FLT 3突变之间存在差异。因此，我们打算确定不同的FLT 3抑制剂是否会产生不同的继发性FLT 3耐药突变谱。使用基于细胞的筛选方法，我们产生了对FLT 3抑制剂SU 5614、PKC 412和索拉非尼耐药的FLT 3-内部串联重复（ITD）表达细胞系。有趣的是，SU 5614出现的耐药突变谱仅限于激酶结构域第二部分（TK 2）的交换，其中D835的交换占主导地位。相比之下，PKC 412仅在酪氨酸激酶结构域1（TK 1）的N676位产生突变。最近在一个PKC 412耐药的AML病例中报告了N676突变。TK 1突变对SU 5614、索拉非尼和舒尼替尼表现出不同的反应，但对PKC 412的反应强烈受损。用SU 5614鉴定的TK 2交换对PKC 412、舒尼替尼或索拉非尼敏感，但Y842 D除外，其引起对索拉非尼的强烈耐药性。值得注意的是，索拉非尼还产生了高度不同的耐药突变谱，与SU 5614或PKC 412没有重叠，包括TK 1中的F691 L和TK 2的Y842位交换。因此，不同的FLT 3激酶抑制剂产生不同的，不重叠的耐药谱。这与Bcr-Abl激酶抑制剂如伊马替尼、尼洛替尼和达沙替尼相反，它们显示出重叠的耐药谱。因此，FLT 3抑制剂的组合可用于在FLT 3-ITD阳性AML的情况下预防FLT 3耐药突变。[Cancer Res 2009;69（7）：3032-41]
FMS-like tyrosine kinase 3 (FLT3) inhibitors have shown activity in the treatment of acute myelogenous leukemia (AML). Secondary mutations in target kinases can cause clinical resistance to therapeutic kinase inhibition. We have previously shown that sensitivity toward tyrosine kinase inhibitors varies between different activating FLT3 mutations. We therefore intended to determine whether different FLT3 inhibitors would produce distinct profiles of secondary, FLT3 resistance mutations. Using a cell-based screening approach, we generated FLT3-internal tandem duplication (ITD)-expressing cell lines resistant to the FLT3 inhibitors SU5614, PKC412, and sorafenib. Interestingly, the profile of resistance mutations emerging with SU5614 was limited to exchanges in the second part of the kinase domain (TK2) with exchanges of D835 predominating. In contrast, PKC412 exclusively produced mutations within tyrosine kinase domain 1 (TK1) at position N676. A mutation at N676 recently has been reported in a case of PKC412-resistant AML. TK1 mutations exhibited a differential response to SU5614, sorafenib, and sunitinib but strongly impaired response to PKC412. TK2 exchanges identified with SU5614 were sensitive to PKC412, sunitinib, or sorafenib, with the exception of Y842D, which caused a strong resistance to sorafenib. Of note, sorafenib also produced a highly distinct profile of resistance mutations with no overlap to SU5614 or PKC412, including F691L in TK1 and exchanges at position Y842 of TK2. Thus, different FLT3 kinase inhibitors generate distinct, nonoverlapping resistance profiles. This is in contrast to Bcr-Abl kinase inhibitors such as imatinib, nilotinih, and dasatinib, which display overlapping resistance profiles. Therefore, combinations of FLT3 inhibitors may be useful to prevent FLT3 resistance mutations in the setting of FLT3-ITD-positive AML. [Cancer Res 2009;69(7):3032-41]