Inhibition of Hsp90 suppresses PI3K/AKT/mTOR signaling and has antitumor activity in Burkitt lymphoma Journal Article
| Authors: | Giulino-Roth, L.; van Besien, H. J.; Dalton, T.; Totonchy, J. E.; Rodina, A.; Taldone, T.; Bolaender, A.; Erdjument-Bromage, H.; Sadek, J.; Chadburn, A.; Barth, M. J.; Dela Cruz, F. S.; Rainey, A.; Kung, A. L.; Chiosis, G.; Cesarman, E. |
| Article Title: | Inhibition of Hsp90 suppresses PI3K/AKT/mTOR signaling and has antitumor activity in Burkitt lymphoma |
| 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. ©2017 AACR. |
| Journal Title: | Molecular Cancer Therapeutics |
| Volume: | 16 |
| Issue: | 9 |
| ISSN: | 1535-7163 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2017-09-01 |
| Start Page: | 1779 |
| End Page: | 1790 |
| Language: | English |
| DOI: | 10.1158/1535-7163.mct-16-0848 |
| PROVIDER: | scopus |
| PMCID: | PMC5587381 |
| PUBMED: | 28619753 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 October 2017 -- Source: Scopus |
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