Second Generation mTOR Inhibitors as a Double-Edged Sword in Malignant Glioma Treatment.

Dennis Heinzen,Joachim P Steinbach,Nadja I Lorenz,Iris Divé,Michael W Ronellenfitsch,Anna-Luisa Luger

doi:10.3390/ijms20184474

Abstract

Glioblastomas (GBs) frequently display activation of the epidermal growth factor receptor (EGFR) and mammalian target of rapamycin (mTOR). mTOR exists as part of two multiprotein complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2). In GBs, mTORC1 inhibitors such as rapamycin have performed poorly in clinical trials, and in vitro protect GB cells from nutrient and oxygen deprivation. Next generation ATP-competitive mTOR inhibitors with affinity for both mTOR complexes have been developed, but data exploring their effects on GB metabolism are scarce. In this study, we compared the ATP-competitive mTORC1/2 inhibitors torin2, INK-128 and NVP-Bez235 to the allosteric mTORC1 inhibitor rapamycin under conditions that mimic the glioma microenvironment. In addition to inhibiting mTORC2 signaling, INK-128 and NVP-Bez235 more effectively blocked mTORC1 signaling and prompted a stronger cell growth inhibition, partly by inducing cell cycle arrest. However, under hypoxic and nutrient-poor conditions mTORC1/2 inhibitors displayed even stronger cytoprotective effects than rapamycin by reducing oxygen and glucose consumption. Thus, therapies that arrest proliferation and inhibit anabolic metabolism must be expected to improve energy homeostasis of tumor cells. These results mandate caution when treating physiologically or therapeutically induced hypoxic GBs with mTOR inhibitors.

Highlights

Despite significant advances in molecular tumor characterization, and increasing knowledge on tumor biology, the prognosis of patients diagnosed with glioblastoma (GB) remains poor [1]
INK-128 and NVP-Bez235 sufficiently inhibited phosphorylation of mammalian target of rapamycin (mTOR) target proteins n-myc downstream regulated gene 1 (NDRG1) and S6 ribosomal protein (S6RP) at concentrations of 100 and 10 nM, respectively (Figure 1a). This coincided with the conversion of microtubule-associated protein 1A/1B-light chain three-I (LC3-I) to LC3-II, an indicator for the initiation of autophagy by mTOR inhibition
Everolimus, an allosteric mTOR inhibitor, even produced detrimental effects leading to shorter overall survival in the RTOG 0913 trial [15]

Summary

Introduction

Despite significant advances in molecular tumor characterization, and increasing knowledge on tumor biology, the prognosis of patients diagnosed with glioblastoma (GB) remains poor [1]. By phosphorylating the eukaryotic translation initiation factor 4E binding protein 1 (4EBP1), and the ribosomal S6 kinase 1 (S6K1), which in turn phosphorylates the S6 ribosomal protein (S6RP), mTORC1 activates a downstream cascade that leads to increased protein translation via factors such as the eukaryotic translation initiation factor 4E (eIF4E) (Figure S1) [4,5]. Another downstream target of mTORC1 is the UNC-51-like kinase 1 (ULK1). An important downstream target of mTORC2 is the n-myc downstream regulated gene 1 (NDRG1) which has been implicated to play a role in cancer metastasis [7] and confer resistance to chemotherapy in malignant glioma [8]

Methods

Results

Conclusion