Heat shock protein 90 (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 the current study we evaluated Hsp90 as a potential therapeutic target in Burkitt lymphoma. We found that primary BL tumors overexpress Hsp90 and that Hsp90 inhibition has anti-tumor 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. Lastly, 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.

<p>IPA analysis of Hps90 client protein networks</p>

<p>BL PDX tumors retain characteristics of primary BL.</p>

<p>BL tumors overexpress Hsp90</p>

<p>PU-H71 suppresses tumor growth in a Ramos xenograft Model.</p>