Inhibition of focal adhesion kinase as a potential therapeutic strategy for imatinib-resistant gastrointestinal stromal tumor
Inhibition of focal adhesion kinase as a potential therapeutic strategy for imatinib-resistant gastrointestinal stromal tumor
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DOI：
10.1158/1535-7163.mct-08-0884
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发表时间：
2009-01-01
影响因子：
5.7
通讯作者：
Naomoto, Yoshio
中科院分区：
文献类型：
--
作者：
Sakurama, Kazufumi;Noma, Kazuhiro;Naomoto, Yoshio
粘着斑激酶（Focal adhesion kinase，FAK）在胃肠道间质瘤（gastrointestinal stromal tumor，GIST）等多种恶性肿瘤中表达上调，其过表达与肿瘤进展及预后不良有关。众所周知，GIST具有c-KIT突变;因此，特定的c-KIT抑制剂（伊马替尼）被认为是GIST的一线化疗药物，尽管某些类型的c-KIT突变由于尚不确定的分子机制而显示出对伊马替尼的耐药性。为了评估c-KIT突变相关的细胞对伊马替尼的反应变化，用伊马替尼或FAK抑制剂（TAE 226）处理稳定转导不同类型c-KIT突变的小鼠淋巴细胞衍生的Ba/F3细胞，并在体外和体内测定其抗肿瘤作用。在体外和体内，轴突11处的突变（KITdel 559 -560）显示出对伊马替尼的高敏感性，而外显子17处的突变（KIT 820 Tyr）显示出对伊马替尼的显著抗性。KIT 820 Tyr细胞在伊马替尼处理下似乎维持FAK和AKT的活性，这表明FAK可能在伊马替尼耐药细胞的存活中起作用。当这些细胞中的FAK活性被TAE 226抑制时，细胞生长受到同等抑制，并且无论c-KIT突变类型如何，细胞都经历了凋亡。口服给予TAE 226显著减少了携带KIT 820 Tyr异种移植物的裸鼠中的肿瘤生长。总之，外显子17的c-KIT突变显示出对伊马替尼的耐药性，并维持FAK激活和随后的生存信号。靶向FAK可能是伊马替尼耐药GIST的潜在治疗策略。[Mol癌症治疗2009;8（1）：127 - 34]
Focal adhesion kinase (FAK) is often up-regulated in a variety of malignancies, including gastrointestinal stromal tumor (GIST), and its overexpression seems to be associated with tumor progressiveness and poor prognosis. GIST is well known to have a mutation to c-KIT; thus, a specific c-KIT inhibitor (imatinib) is recognized as the first-line chemotherapy for GIST, although a certain type of c-KIT mutation reveals a resistance to imatinib due to as yet uncertain molecular mechanisms. To assess the c-KIT mutation-related variation of cellular responses to imatinib, murine lymphocyte-derived Ba/F3 cells, which are stably transduced with different types of c-KIT mutation, were treated with either imatinib or a FAK inhibitor (TAE226), and their antitumor effects were determined in vitro and in vivo. A mutation at axon 11 (KITdel559-560) displayed a high sensitivity to imatinib, whereas that at exon 17 (KIT820Tyr) showed a significant resistance to imatinib in vitro and in vivo. KIT820Tyr cells appeared to maintain the activities of FAK and AKT under the imatinib treatment, suggesting that FAK might play a role in cell survival in imatinib-resistant cells. When FAK activity in those calls was inhibited by TAE226, cell growth was equally suppressed and the cells underwent apoptosis regardless of the c-KIT mutation types, Oral administration of TAE226 significantly diminished tumor growth in nude mice bearing KIT820Tyr xenografts. In summary, c-KIT mutation at exon 17 displayed a resistance to imatinib with maintained activations of FAK and subsequent survival signals. Targeting FAK could be a potential therapeutic strategy for imatinib-resistant GISTs. [Mol Cancer Ther 2009;8(1):127 - 34]