The BET bromodomain protein BRD4 represents as a promising drug target for High-grade Serous Ovarian Carcinoma (HGSOC) due to its role in promoting cancer cell growth and survival. Importantly, several studies have shown that HGSOC cell lines and tumor models are very sensitive to BRD4 inhibition, and these drugs are moving rapidly towards the clinic. Of particular interest, a revolutionary new class of BRD4 drugs has just been discovered that can selectively remove or degrade BRD4 proteins from cancer cells. These PROTACs (Proteolysis-Targeting Chimeras), highjack the cancer cells protein machinery, effectively tricking the cancer cell into degrading BRD4. BRD4-PROTACs have been shown to be superior at killing cancer cells than traditional small molecule bromodomain inhibitors of BRD4, representing the more favorable BRD4 therapy to pursue clinically. However, currently little is known about the effectiveness of BRD4-PROTACs in HGSOC cells, nor the potential resistance mechanisms cancer cells will use to overcome these new drugs. Our recent findings showed BRD4-PROTACs were superior at killing HGSOC cells than traditional BRD4 inhibitors. However, we discovered the majority of HGSOC cell lines acquired resistance to BRD4-PROTACs. Remarkably, HGSOC cells upregulated a network of proteins that led to the activation of the protein kinase MTOR. Activation of MTOR prevented BRD4 from being degraded by PROTACs causing drug resistance. Importantly, treatment of HGSOC resistant cells with MTOR inhibitors resulted in the rapid degradation of BRD4 causing cell death. Moreover, we found combining BRD4-PROTACs and MTOR inhibitors significantly improved the killing of HGSOC cells, supporting this drug combination for the treatment of HGSOC.
In the proposed studies, we will evaluate the effectiveness of our rationally-predicted drug combination therapy involving BRD4-PROTACs and MTOR inhibitors to cause tumor regression in animal models of HGSOC. If successful, these in vivo studies will provide the therapeutic proof-of-concept for the use of this novel drug combination therapy to treat HGSOC, which will be avidly pursued in a phase I trial at FCCC. Additionally, we will investigate the mechanisms by which MTOR protects BRD4 from PROTAC degradation in HGSOC cells. Together, the proposed studies will lay the groundwork for future clinical trials aiming to maximize the antitumor activity of BRD4 PROTACs and evaluate mechanisms conveying resistance to this revolutionary new class of drugs.