A systems approach identifies cooperative targeting of MYC by combined mTOR/HDAC inhibition for cancer treatment

Tuesday, September 23, 2014 — Poster Session III
12:00 p.m. – 2:00 p.m.	FAES Academic Center	NCI	PHARM-3

* FARE Award Winner

Authors

• J.K. Simmons
• A.M. Michalowski
• B.J. Gamache
• W. DuBois
• J.M. Gary
• J. Patel
• K. Zhang
• S. Zhang
• J. Huang
• B.A. Mock

Abstract

Elucidating synergistic mechanisms of molecularly targeted treatment combinations in the context of highly complex oncogenic networks remains challenging. We mechanistically evaluated the synergistic mTORi/HDACi combination in multiple myeloma (MM) with an integrated analytic workflow by transcriptional co-expression analysis to define the combination response network, patient dataset integration to identify potential disease-specific activity, and upstream regulator analysis to uncover potential regulatory nodes. MYC was identified as a potential regulator of the disease-related, mTORi/HDACi cooperative expression module. This finding was supported by ChIP-Seq analysis and experimental confirmation of the MYC-driven expression of this module, and the importance of MYC for the activity of the combination. mTORi/HDACi treatment cooperatively inhibited MYC protein expression by decreasing its stability. mTORi/HDACi extinguished MYC protein expression in a mouse model of plasma cell dyscrasias and substantially increased overall survival. Our comprehensive, data-rich approach to understanding drug synergy has identified a clinically actionable strategy to inhibit oncogenic MYC activity.

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