Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, D820, 44 Binney Street, Boston, MA 02115, USA.
Cancer Res. 2010 Dec 15;70(24):10038-43. doi: 10.1158/0008-5472.CAN-10-2956. Epub 2010 Oct 28.
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) harboring a RANBP2-ALK translocation who progressed while on 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, and the HSP90 inhibitor 17-AAG are both effective in models harboring 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.
ALK 激酶抑制剂克唑替尼（PF-02341066）在 ALK 易位癌症患者中具有临床疗效，但最终其疗效将受到获得性耐药的限制。在这里，我们报告了 ALK 中的一个继发突变 F1174L 的鉴定，这是导致携带 RANBP2-ALK 易位的炎性肌纤维母细胞瘤（IMT）患者在克唑替尼治疗过程中进展时出现克唑替尼耐药的原因之一。当与 ALK 易位位于顺式时，该突变（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的增加。此外，F1174L 突变抑制了克唑替尼介导的 ALK 信号下调，并阻止了 RANBP2-ALK Ba/F3 细胞的凋亡。一种化学上不同的 ALK 抑制剂 TAE684 和 HSP90 抑制剂 17-AAG 在携带 F1174L ALK 突变的模型中均有效。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。
