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Functional role and therapeutic targeting of p21-activated kinase 4 in multiple myeloma

Mariateresa Fulciniti, Joaquin Martinez-Lopez, William Senapedis, Stefania Oliva, Rajya Lakshmi Bandi, Nicola Amodio, Yan Xu, Raphael Szalat, Annamaria Gulla, Mehmet K. Samur, Aldo Roccaro, Maria Linares, Michele Cea, Erkan Baloglu, Christian Argueta, Yosef Landesman, Sharon Shacham, Siyuan Liu, Monica Schenone, Shiaw-Lin Wu, Barry Karger, Rao Prabhala, Kenneth C. Anderson and Nikhil C. Munshi

Key Points

  • High expression of PAK4 promotes myeloma cell proliferation through activation of MM antiapoptotic and survival pathways.

  • Targeting PAK4 with a novel small molecule inhibitor, KPT-9274, has significant impact on MM cell growth and survival.

Publisher's Note: There is an Inside Blood Commentary on this article in this issue.

Abstract

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.

  • Submitted June 27, 2016.
  • Accepted December 16, 2016.
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