Abstract
XPO1 has recently emerged as a viable treatment target for solid malignancies, including glioblastoma (GBM), the most common primary malignant brain tumor in adults. However, given that tumors become commonly resistant to single treatments, the identification of combination therapies is critical. Therefore, we tested the hypothesis that inhibition of anti-apoptotic Bcl-2 family members and XPO1 are synthetically lethal. To this purpose, two clinically validated drug compounds, the BH3-mimetic, ABT263, and the XPO1 inhibitor, Selinexor, were used in preclinical GBM model systems. Our results show that inhibition of XPO1 reduces cellular viability in glioblastoma cell cultures. Moreover, addition of ABT263 significantly enhances the efficacy of XPO1 inhibition on the reduction of cellular viability, which occurs in a synergistic manner. While selinexor inhibits the proliferation of glioblastoma cells, the combination treatment of ABT263 and selinexor results in substantial induction of cell death, which is accompanied by activation of effector- initiator caspases and cleavage of PARP. Mechanistically we find that XPO1 inhibition results in down-regulation of anti-apoptotic Mcl-1 and attenuates ABT263 driven Mcl-1 up-regulation. Consistently, siRNA mediated silencing of Mcl-1 sensitizes for ABT263 mediated cell death and partially for the combination treatment. By using a human patient-derived xenograft model of glioblastoma in mice, we demonstrate that the combination treatment of ABT263 and Selinexor reduces tumor growth significantly more than each compound alone. Collectively, these results suggest that inhibition of XPO1 and Bcl-2/Bcl-xL might be a potential strategy for the treatment of malignant glial tumors.
Highlights
The purpose of this study is the characterization of a novel treatment strategy for glioblastoma, a primary glial brain tumor that despite significant scientific progress still has a bad prognosis
XPO1 has been established as a potential drug target for malignant glial brain tumors, we still interrogated the TCGA data base for low grade gliomas to assess as to whether or not XPO1 mRNA levels have a prognostic impact on patients with low grade gliomas
Our findings indicate that increasing concentrations of selinexor reduce the proliferation of glioblastoma cell cultures (GBM12, which was most efficient in LN229 GBM cells (Fig. 1A)
Summary
The purpose of this study is the characterization of a novel treatment strategy for glioblastoma, a primary glial brain tumor that despite significant scientific progress still has a bad prognosis In this context, XPO11,2 has been suggested as a target for glioblastoma since recently it was shown that the compound selinexor is capable of crossing the blood brain barrier and extends survival in patient-derived orthotopic glioblastoma xenograft models[3]. The major disadvantage is that solid tumors often rely either on Bcl-xL or a combination of both Bcl-2 and Bcl-xL for their survival The former compound ABT263 remains still a desirable drug candidate since it dually inhibits Bcl-xL and Bcl-2 and it has reached clinical testing as well. We demonstrate that the combination treatment of ABT263 and Selinexor reduces cellular viability and tumor growth synergistically in vitro and in a patient-derived xenograft model of glioblastoma
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