Phosphoinositide Protein Kinase PDPK1 Is a Crucial Cell Signaling Mediator in Multiple Myeloma

Abstract

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. Cancer Res; 74(24); 7418-29. Ó2014 AACR.

Novel therapeutic strategies for multiple myeloma

“…Importantly, this pathway is upregulated by Akt inhibition, and dual inhibition of both pathways using Akt inhibitors and MEK inhibitors shows synergistic anti-tumor effects [70, 72, 83]. More recently, 3-phosphoinositide–dependent protein kinase 1 (PDPK1) inhibitor has been shown to induce growth inhibition and apoptosis in MM cells through blockade of both RSK2, a mediator of MAPK/ERK pathway, and Akt [84], further indicating potential clinical utility.…”

PDK1 inhibitor GSK2334470 exerts antitumor activity in multiple myeloma and forms a novel multitargeted combination with dual mTORC1/C2 inhibitor PP242

“…Recently, several lines of evidence indicate that PDK1 can be considered as a promising target for anticancer drugs and various classes of small molecular inhibitor targeting PDK1 have been proposed [32–34]. In MM, PDK1 is generally active and higher expression than other hematopoietic lineages [17, 35, 36]. Activation of PDK1 is essential for myelomagenesis by regulating RSK2, AKT, c-MYC, IRF4 or cyclin Ds, which accelerates the drug resistance and the disease progression [17].…”

“…Indeed, it has been recently shown that GSK2334470 (GSK-470), a novel and highly specific inhibitor of PDK1 [13], inhibits growth, induces cell cycle arrest and overcomes drug resistance in human cancer cells [14–16]. In MM, it was demonstrated that PDK1 is expressed and active in all eleven MM-derived cell lines, regardless of the type of cytogenetic abnormality or the status of upstream signaling molecules, and that genetic or pharmacological (BX-912) inhibition of PDK1 caused the growth inhibition and the induction of apoptosis, and augmented the in vitro cytotoxic effects of antimyeloma agents such as melphalan, etoposide, or bortezomib [17]. …”

Patent Highlights October–November 2016

“…In some embodiments, the therapeutic inhibitor (i.e., X-chromosome reactivator) is a selective mTOR inhibitor such as rapamycin, KU-0063794 or everolimus. Many of these targets are downstream substrates of PDPK1, a phosphoinositide protein kinase that regulates PI3K/AKT signaling, and is involved in cancer progression [22]. Extensive biological data show that all these combinations reactivate expression of MECP2 in vitro and in mouse models.…”