Format

Send to

Choose Destination
Mol Cancer Ther. 2017 Sep;16(9):1779-1790. doi: 10.1158/1535-7163.MCT-16-0848. Epub 2017 Jun 15.

Inhibition of Hsp90 Suppresses PI3K/AKT/mTOR Signaling and Has Antitumor Activity in Burkitt Lymphoma.

Author information

1
Department of Pediatrics, Weill Cornell Medical College, New York, New York. lgr2002@med.cornell.edu.
2
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York.
3
Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, New York.
4
Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
5
Department of Pediatrics, Roswell Park Cancer Institute, Buffalo, New York.
6
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.

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.

PMID:
28619753
PMCID:
PMC5587381
DOI:
10.1158/1535-7163.MCT-16-0848
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center