Data from HSP90 Inhibition Overcomes Resistance to Molecular Targeted Therapy in <i>BRAF<sup>V600E</sup></i>-mutant High-grade Glioma

Abstract

<div>AbstractPurpose:<p>Molecular targeted therapy using BRAF and/or MEK inhibitors has been applied to <i>BRAF<sup>V600E</sup></i>-mutant high-grade gliomas (HGG); however, the therapeutic effect is limited by the emergence of drug resistance.</p>Experimental Design:<p>We established multiple paired <i>BRAF<sup>V600E</sup></i>-mutant HGG patient-derived xenograft models based on tissues collected prior to and at relapse after molecular targeted therapy. Using these models, we dissected treatment-resistant mechanisms for molecular targeted therapy and explored therapeutic targets to overcome resistance in <i>BRAF<sup>V600E</sup></i> HGG models <i>in vitro</i> and <i>in vivo</i>.</p>Results:<p>We found that, despite causing no major genetic and epigenetic changes, BRAF and/or MEK inhibitor treatment deregulated multiple negative feedback mechanisms, which led to the reactivation of the MAPK pathway through c-Raf and AKT signaling. This altered oncogenic signaling primarily mediated resistance to molecular targeted therapy in <i>BRAF<sup>V600E</sup></i>-mutant HGG. To overcome this resistance mechanism, we performed a high-throughput drug screening to identify therapeutic agents that potently induce additive cytotoxicity with BRAF and MEK inhibitors. We discovered that HSP90 inhibition combined with BRAF/MEK inhibition coordinately deactivated the MAPK and AKT/mTOR pathways, and subsequently induced apoptosis via dephosphorylation of GSK3β (Ser9) and inhibition of Bcl-2 family proteins. This mediated potent cytotoxicity <i>in vitro</i> and <i>in vivo</i> in refractory models with acquired resistance to molecular targeted therapy.</p>Conclusions:<p>The combination of an HSP90 inhibitor with BRAF or MEK inhibitors can overcome the limitations of the current therapeutic strategies for <i>BRAF<sup>V600E</sup></i>-mutant HGG.</p></div>