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Giulino-Roth, Lisa; van Besien, Herman J; Dalton, Tanner; Totonchy, Jennifer E; Rodina, Anna; Taldone, Tony; Bolaender, Alexander; Erdjument-Bromage, Hediye; Sadek, Jouliana; Chadburn, Amy; Barth, Matthew J; Dela Cruz, Filemon S; Rainey, Allison; Kung, Andrew L; Chiosis, Gabriela; Cesarman, Ethel
Molecular cancer therapeutics, 09/2017, Volume: 16, Issue: 9Journal Article
Hsp90 is a molecular chaperone that protects proteins, including oncogenic signaling complexes, from proteolytic degradation. PU-H71 is a next-generation Hsp90 inhibitor that preferentially targets the functionally distinct pool of Hsp90 present in tumor cells. Tumors that are driven by the MYC oncoprotein may be particularly sensitive to PU-H71 due to the essential role of Hsp90 in the epichaperome, which maintains the malignant phenotype in the setting of MYC. Burkitt lymphoma (BL) is an aggressive B-cell lymphoma characterized by MYC dysregulation. In this study, we evaluated Hsp90 as a potential therapeutic target in BL. We found that primary BL tumors overexpress Hsp90 and that Hsp90 inhibition has antitumor activity and , including potent activity in a patient-derived xenograft model of BL. To evaluate the targets of PU-H71 in BL, we performed high-affinity capture followed by proteomic analysis using mass spectrometry. We found that Hsp90 inhibition targets multiple components of PI3K/AKT/mTOR signaling, highlighting the importance of this pathway in BL. Finally, we found that the anti-lymphoma activity of PU-H71 is synergistic with dual PI3K/mTOR inhibition and Overall, this work provides support for Hsp90 as a therapeutic target in BL and suggests the potential for combination therapy with PU-H71 and inhibitors of PI3K/mTOR. .
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