TIC10/ONC201 synergizes with Bcl-2/Bcl-xL inhibition in glioblastoma by suppression of Mcl-1 and its binding partners in vitro and in vivo.

Georg Karpel-Massler,Markus D Siegelin,Mike-Andrew Westhoff,Marc-Eric Halatsch,Maïmouna Bâ,Peter Canoll,Chang Shu,Jeffrey N Bruce

doi:10.18632/oncotarget.5505

Georg Karpel-Massler, Markus D Siegelin + Show 6 more

Open Access

https://doi.org/10.18632/oncotarget.5505

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Abstract

Glioblastoma is the most frequent primary brain tumor in adults. Current therapeutic options are sparse and the prognosis of patients suffering from this disease is grim. Abundance in intratumoral heterogeneity among different deregulated signaling pathways is a hallmark of glioblastoma and likely accounts for its recurrence and resistance to treatment. Glioblastomas harbor a plethora of deregulated pathways driving tumor formation and growth. In this study, we show that TIC10/ONC201, a promising compound that is currently in planned clinical development, along with Bcl-2/Bcl-xL inhibition by ABT263 yields a strong synergistic antiproliferative effect on pediatric, adult, proneural glioblastoma and glioma stem-like cells. On the molecular level, treatment with TIC10/ONC201 results in a posttranslational decrease of the anti-apoptotic Bcl-2 family member, myeloid cell leukemia 1 (Mcl-1), through modulation of the chaperone Bag3 and the deubiquitinase Usp9X. Consistently, the combination treatment of TIC10/ONC201 and ABT263 required the presence of functional BAX and BAK to drive intrinsic apoptosis, but is surprisingly independent of the extrinsic apoptotic pathway. Moreover, the expression of Noxa protein was required for efficient apoptosis induction by TIC10/ONC201 and ABT263. Importantly, the drug combination of TIC10/ONC201 and the BH3-mimetic, ABT263, led to a regression of tumors in vivo, without any notable toxicity and side effects. Overall, TIC10/ONC201 along with Bcl-2/Bcl-xL inhibition holds significant promise as a novel potential approach for the treatment of recalcitrant tumors such as glioblastoma.

Highlights

For many solid tumor entities including glioblastoma, efficient therapeutic strategies still do not exist
Allen et al showed that treatment with TIC10/ONC201 resulted in dual inhibition of AKT and ERK signaling followed by dephosphorylation of Foxo3a, subsequent nuclear translocation and enhanced transcription of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)
From a mechanistic point of view, we identified downregulation of Usp9X as well as Bag3 followed by enhanced myeloid cell leukemia 1 (Mcl-1)-degradation as one of the driving mechanisms subjacent to the profound anti-cancer activity inherent to a combined inhibition of ERK signaling and B-cell lymphoma-2 (Bcl-2)/Bcl-xL

Summary

Introduction

For many solid tumor entities including glioblastoma, efficient therapeutic strategies still do not exist. It seems unlikely that concomitant activation of different proneoplastic signaling pathways, which vary among different cancer cells within the same tumor, will be successfully addressed by one “magic bullet”. TIC10/ONC201 provides several favorable characteristics with respect to a potential future clinical application such as its capacity to cross the blood-brain barrier and a preserved activity when administered orally [8]. These features render the compound interesting for combinatorial therapeutic strategies targeting brain tumors

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