Functional role and therapeutic targeting of p21-associated kinase 4 (PAK4) in multiple myeloma
Menée sur des lignées cellulaires de myélome multiple, cette étude met en évidence des mécanismes par lesquels la kinase PAK4 exerce une fonction d'oncogène
High expression of PAK4 promotes myeloma cell proliferation through activation of MM anti-apoptotic and survival pathways.Targeting PAK4 with a novel small molecule inhibitor, KPT-9274 has significant impact on MM cell growth and survival. 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-ERK 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. These data support PAK4 as an oncogene in myeloma, and provide the rationale for the clinical evaluation of PAK4 modulator in myeloma.