Functional role and therapeutic targeting of p21-activated kinase 4 in multiple myeloma
Functional role and therapeutic targeting of p21-activated kinase 4 in multiple myeloma
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DOI：
10.1182/blood-2016-06-724831
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发表时间：
2017-04-20
期刊：
影响因子：
20.3
通讯作者：
Munshi, Nikhil C.
中科院分区：
文献类型：
--
作者：
Fulciniti, Mariateresa;Martinez-Lopez, Joaquin;Munshi, Nikhil C.
失调的致癌丝氨酸/苏氨酸激酶在多种形式的恶性肿瘤（包括多发性骨髓瘤（MM））中发挥病理作用，因此代表潜在的治疗靶点。在这里，我们评估了p21激活激酶4（PAK 4）的生物学和功能作用及其作为MM临床应用新靶点的潜力。PAK 4通过激活MM存活信号通路（包括MEK-细胞外信号调节激酶通路）促进MM细胞生长和存活。此外，用口服生物可利用的PAK 4变构调节剂（KPT-9274）处理显著影响了大组MM细胞系和单独的原代MM细胞中以及在骨髓微环境存在下的MM细胞生长和存活。有趣的是，我们已经将FGFR 3鉴定为PAK 4的新型结合伴侣，并观察到KPT-9274对t（4;14）阳性MM细胞的显著活性。这组数据支持PAK 4作为骨髓瘤中的致癌基因，并为PAK 4调节剂在骨髓瘤中的临床评价提供了依据。
Dysregulated oncogenic serine/threonine kinases play a pathological role in diverse forms of malignancies, including multiple myeloma (MM), and thus represent potential therapeutic targets. Here, we evaluated the biological and functional role of p21-activated kinase 4 (PAK4) and its potential as a new target in MM for clinical applications. PAK4 promoted MM cell growth and survival via activation of MM survival signaling pathways, including the MEK-extracellular signal-regulated kinase pathway. Furthermore, treatment with orally bioavailable PAK4 allosteric modulator (KPT-9274) significantly impacted MM cell growth and survival in a large panel of MM cell lines and primary MM cells alone and in the presence of bone marrow microenvironment. Intriguingly, we have identified FGFR3 as a novel binding partner of PAK4 and observed significant activity of KPT-9274 against t(4;14)-positive MM cells. This set of data supports PAK4 as an oncogene in myeloma and provide the rationale for the clinical evaluation of PAK4 modulator in myeloma.