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

Chunmei Yang,Xianbo Huang,Hui Liu,Wenbin Qian,Jueying Wei,Liangshun You,Feng Xiao

doi:10.18632/oncotarget.16642

Abstract

A deeper understanding of the complex pathogenesis of multiple myeloma (MM) continues to lead to novel therapeutic approaches. Prior studies suggest that 3-phosphoinositide-dependent kinase 1 (PDK1) is expressed and active, acting as a crucial regulator of molecules that are essential for myelomagenesis. In the present study, we show that GSK2334470 (GSK-470), a novel and highly specific inhibitor of PDK1, induces potent cytotoxicity in MM cell lines including Dexamethasone-resistant cell line, but not in human normal cells. Insulin-like growth factor-1 could not rescue GSK-470-induced cell death. Moreover, GSK-470 down-modulates phosphor-PDK1, thereby inhibiting downstream phosphor-AKT at Thr308 and mTOR complex 1 (mTORC1) activity. However, GSK-470 could not affect mTORC2 activity and phosphor-AKT at Ser473. RPMI 8226 and OPM-2 cells with low expression of PTEN show relative resistant to GSK-470. Knockout of PTEN by shRNA resulted in a partial reversion of GSK-470-mediated growth inhibition, whereas overexpression of PTEN enhanced myeloma cell sensitivity to GSK-470, suggesting that the sensitivity to GSK-470 is correlated with PTEN expression statue in MM cells. Combining PP242, a dual mTORC1/C2 inhibitor, with GSK-470, had greater antimyeloma activity than either one alone in vitro and in MM xenograft model established in immunodeficient mice. In particular, this combination was able to result in a complete inhibition of mTORC1/C2 and full activity of AKT. Together, these findings raise the possibility that combining PDK1 antagonist GSK-470 with mTORC1/C2 inhibitors may represent a novel strategy against MM including drug-resistant myeloma, regardless of PTEN expression status.

Highlights

Multiple myeloma (MM) is a molecularly/ symptomatically heterogeneous B-cell malignancy characterized by the accumulation of clonal malignant plasma in bone marrow [1]
Given the facts that GSK-470 failed to inhibit phospho-mTOR at Ser2448 and its downstream phosphoAKT (Ser473), which was demonstrated in this study, and that dual mTOR complex 1 (mTORC1)/C2 inhibitors is much more active than mTORC1 inhibition alone in myeloma cells [27], we examined whether PP242, a non-rapalog agent that targets simultaneously mTORC1 and mTOR complex 2 (mTORC2) [28], enhances GSK-470-mediated cell death
phosphoinositide-dependent kinase 1 (PDK1) plays a pivotal role in modulating PI3Kpathway signaling, and is involved in the regulation of cell metabolism, proliferation, and survival of tumor cells [30, 31]

Summary

Introduction

Multiple myeloma (MM) is a molecularly/ symptomatically heterogeneous B-cell malignancy characterized by the accumulation of clonal malignant plasma in bone marrow [1]. The U.S Food and Drug Administration (FDA) approved for use in MM two monoclonal antibodies, daratumumab and elotuzumab, both directed against glycoproteins expressed on the surface of MM cells [5, 6]. Despite these significant improvements, the cure of patients with MM remains challenging and difficult. In MM, aberrant activation of several signal transduction pathways results in cellular proliferation and drug-resistance of tumor cells [1] These signaling cascades may be attractive targets for the development of innovative therapeutic strategies for MM patients. In MM, it was demonstrated that PDK1 is expressed and active in all eleven MMderived cell lines, regardless of the type of cytogenetic abnormality or the status of upstream signaling molecules, and that genetic or pharmacological (BX912) 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]

Methods

Results

Conclusion