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

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Bibliographische Detailangaben
Zeitschriftentitel:	Molecular Cancer Therapeutics
Personen und Körperschaften:	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
In:	Molecular Cancer Therapeutics, 16, 2017, 9, S. 1779-1790
Format:	E-Article
Sprache:	Englisch
veröffentlicht:	American Association for Cancer Research (AACR)
Schlagwörter:	Cancer Research Oncology

Details
Zusammenfassung:	<jats:title>Abstract</jats:title> <jats:p>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.</jats:p>
Umfang:	1779-1790
ISSN:	1535-7163 1538-8514
DOI:	10.1158/1535-7163.mct-16-0848