Inhibition of Hsp90 suppresses PI3K/AKT/mTOR signaling and has antitumor activity in Burkitt lymphoma

L Giulino-Roth, HJ van Besien, T Dalton… - Molecular cancer …, 2017 - AACR
L Giulino-Roth, HJ van Besien, T Dalton, JE Totonchy, A Rodina, T Taldone, A Bolaender
Molecular cancer therapeutics, 2017AACR
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 …
Abstract
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 in vitro and in vivo, 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 in vitro and in vivo. 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. Mol Cancer Ther; 16(9); 1779–90. ©2017 AACR.
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