The neuroblastoma-associated F1174L ALK mutation causes resistance to an ALK kinase inhibitor in ALK-translocated cancers.
The neuroblastoma-associated F1174L ALK mutation causes resistance to an ALK kinase inhibitor in ALK-translocated cancers.
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DOI：
10.1158/0008-5472.can-10-2956
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发表时间：
2010-12-15
期刊：
影响因子：
11.2
通讯作者：
Jänne PA
中科院分区：
文献类型：
--
作者：
Sasaki T;Okuda K;Zheng W;Butrynski J;Capelletti M;Wang L;Gray NS;Wilner K;Christensen JG;Demetri G;Shapiro GI;Rodig SJ;Eck MJ;Jänne PA
ALK激酶抑制剂crizotinib （PF-02341066）对ALK易位性癌症患者临床有效，但其疗效最终会受到获得性耐药的限制。在这里，我们报告了在一名炎症性肌纤维母细胞肿瘤（IMT）患者中，ALK的继发性突变F1174L的鉴定，这是在克唑替尼治疗期间发生RANBP2-ALK易位的患者对克唑替尼耐药的一个原因。当与ALK易位同时存在时，这种突变（也在神经母细胞瘤中检测到）会导致ALK磷酸化、细胞生长和下游信号传导的增加。此外，F1174L突变抑制克唑替尼介导的ALK信号下调，阻断RANBP2-ALK Ba/F3细胞的凋亡。化学上不同的ALK抑制剂TAE684或HSP90抑制剂17-AAG对携带F1174L ALK突变的模型都有效。我们的研究结果强调了研究耐药机制的重要性，以便为alk易位癌症患者开发有效的临床治疗方法。
The ALK kinase inhibitor crizotinib (PF-02341066) is clinically effective in patients with ALK-translocated cancers, but its efficacy will ultimately be limited by acquired drug resistance. Here we report the identification of a secondary mutation in ALK, F1174L, as one cause of crizotinib resistance in a patient with an inflammatory myofibroblastic tumor (IMT) harbouring a RANBP2-ALK translocation who progressed while crizotinib therapy. When present in cis with an ALK translocation, this mutation (also detected in neuroblastomas) causes an increase in ALK phosphorylation, cell growth and downstream signaling. Furthermore, the F1174L mutation inhibits crizotinib mediated downregulation of ALK signaling and blocks apoptosis in RANBP2-ALK Ba/F3 cells. A chemically distinct ALK inhibitor, TAE684, or the HSP90 inhibitor 17-AAG are both effective in models harbouring the F1174L ALK mutation. Our findings highlight the importance of studying drug resistance mechanisms in order to develop effective clinical treatments for patients with ALK-translocated cancers.