Synergism of FAK and tyrosine kinase inhibition in Ph+ B-ALL
Synergism of FAK and tyrosine kinase inhibition in Ph+ B-ALL
复制标题
DOI：
10.1172/jci.insight.86082
复制
发表时间：
2016-04-07
期刊：
影响因子：
8
通讯作者：
Mullighan, Charles G.
中科院分区：
文献类型：
--
作者：
Churchman, Michelle L.;Evans, Kathryn;Mullighan, Charles G.
BCR-ABL1(+) B祖急性淋巴细胞白血病（Ph+ B- all）是一种侵袭性疾病，通常对现有治疗反应不佳。IKZF1编码淋巴转录因子Ikaros，其改变存在于超过80%的Ph+ ALL中，并与干细胞样表型、异常粘附分子表达和信号传导、白血病细胞粘附到骨髓干细胞生态位以及预后不良相关。在这里，我们发现FAK1在Ph+ B-ALL中上调，并在ikzf1改变的细胞中进一步过表达，并且FAK抑制剂VS-4718有效抑制异常的FAK信号传导和白血病细胞粘附，增强对酪氨酸激酶抑制剂的反应性，诱导体内治愈。因此，用VS-4718靶向FAK是一种有吸引力的方法，可以克服FAK在Ph+ B-ALL中过表达的有害影响，特别是在消除Ikaros改变诱导的粘附表型方面，值得在Ph+ B-ALL的临床试验中进行评估，无论IKZF1状态如何。
BCR-ABL1(+) B progenitor acute lymphoblastic leukemia (Ph+ B-ALL) is an aggressive disease that frequently responds poorly to currently available therapies. Alterations in IKZF1, which encodes the lymphoid transcription factor Ikaros, are present in over 80% of Ph+ ALL and are associated with a stem cell-like phenotype, aberrant adhesion molecule expression and signaling, leukemic cell adhesion to the bone marrow stem cell niche, and poor outcome. Here, we show that FAK1 is upregulated in Ph+ B-ALL with further overexpression in IKZF1-altered cells and that the FAK inhibitor VS-4718 potently inhibits aberrant FAK signaling and leukemic cell adhesion, potentiating responsiveness to tyrosine kinase inhibitors, inducing cure in vivo. Thus, targeting FAK with VS-4718 is an attractive approach to overcome the deleterious effects of FAK overexpression in Ph+ B-ALL, particularly in abrogating the adhesive phenotype induced by Ikaros alterations, and warrants evaluation in clinical trials for Ph+ B-ALL, regardless of IKZF1 status.