Multiple myeloma is a cytogenetically/molecularly heterogeneous
hematologic malignancy that remains mostly incurable, and the identification of a universal and relevant therapeutic target molecule is essential for the further development of therapeutic strategy. Herein, we identified that
3-phosphoinositide-dependent protein kinase 1 (PDPK1), a
serine threonine kinase, is expressed and active in all eleven
multiple myeloma-derived cell lines examined regardless of the type of
cytogenetic abnormality, the mutation state of RAS and FGFR3 genes, or the activation state of ERK and AKT. Our results revealed that PDPK1 is a pivotal regulator of molecules that are essential for myelomagenesis, such as RSK2, AKT, c-MYC, IRF4, or
cyclin Ds, and that PDPK1 inhibition caused the growth inhibition and the induction of apoptosis with the activation of BIM and BAD, and augmented the in vitro cytotoxic effects of antimyeloma agents in myeloma cells. In the clinical setting, PDPK1 was active in myeloma cells of approximately 90% of symptomatic patients at diagnosis, and the smaller population of patients with
multiple myeloma exhibiting myeloma cells without active PDPK1 showed a significantly less frequent proportion of the disease stage III by the International Staging System and a significantly more favorable prognosis, including the longer overall survival period and the longer progression-free survival period by
bortezomib treatment, than patients with active PDPK1, suggesting that PDPK1 activation accelerates the
disease progression and the resistance to treatment in
multiple myeloma. Our study demonstrates that PDPK1 is a potent and a universally targetable signaling mediator in
multiple myeloma regardless of the types of cytogenetic/molecular profiles.