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

Mariateresa Fulciniti1, Joaquin Martinez-Lopez1,2, William Senapedis3

  • 1LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.

Blood
|January 19, 2017
PubMed

Insights

p21-activated kinase 4 (PAK4) drives multiple myeloma (MM) growth by activating survival pathways. Inhibiting PAK4 with KPT-9274 shows promise for treating MM, including specific subtypes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Dysregulated serine/threonine kinases are implicated in multiple myeloma (MM) pathogenesis.
  • Oncogenic kinases represent viable therapeutic targets in various cancers, including MM.

Purpose of the Study:

  • To investigate the role of p21-activated kinase 4 (PAK4) in MM.
  • To evaluate PAK4 as a potential therapeutic target for MM treatment.

Main Methods:

  • Assessed PAK4's role in MM cell proliferation and survival signaling.
  • Utilized the orally bioavailable PAK4 allosteric modulator, KPT-9274, against MM cell lines and primary cells.
  • Investigated the interaction between PAK4 and FGFR3 in MM cells.

Main Results:

  • PAK4 promotes MM cell growth and survival through pathways like MEK-ERK.
  • KPT-9274 effectively inhibited MM cell growth and survival, even within the bone marrow microenvironment.
  • FGFR3 was identified as a novel PAK4 binding partner, with KPT-9274 showing activity against t(4;14)-positive MM cells.

Conclusions:

  • PAK4 functions as an oncogene in multiple myeloma.
  • PAK4 inhibition represents a promising therapeutic strategy for MM, warranting clinical investigation.

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