The BRD9/7 Inhibitor TP-472 Blocks Melanoma Tumor Growth by Suppressing ECM-Mediated Oncogenic Signaling and Inducing Apoptosis.

Abstract

Simple SummaryMelanoma is an aggressive form of skin cancer and the leading cause of skin cancer-related deaths. Current therapies, including those targeting oncogenic pathways and immunotherapies, provide therapeutic benefits to only a subset of melanoma patients. Therefore, more options for therapeutic interventions are needed. Epigenetic alterations play an important role in tumor development and progression. In this study, we identified that TP-472 a small molecule inhibitor of BRD7/9 blocks melanoma tumor growth in cell cultures and in mouse models of melanoma growth. Further studies revealed that TP-472 downregulates cancer-promoting signaling pathways and induces cell death. Thus, this study identifies TP-472 as a potentially useful therapeutic agent for melanoma therapy.Melanoma accounts for the majority of all skin cancer-related deaths and only 1/3rd of melanoma patients with distal metastasis survive beyond five years. However, current therapies including BRAF/MEK targeted therapies or immunotherapies only benefit a subset of melanoma patients due to the emergence of intrinsic or extrinsic resistance mechanisms. Effective treatment of melanoma will thus require new and more effective therapeutic agents. Towards the goal of identifying new therapeutic agents, we conducted an unbiased, druggable epigenetic drug screen using a library of 32 epigenetic inhibitors obtained from the Structural Genome Consortium that targets proteins encoding for epigenetic regulators. This chemical genetic screening identified TP-472, which targets bromodomain-7/9, as the strongest inhibitor of melanoma growth in both short- and long-term survival assays and in mouse models of melanoma tumor growth. Mechanistically, using a transcriptome-wide mRNA sequencing profile we identified TP-472 treatment downregulates genes encoding various extracellular matrix (ECM) proteins, including integrins, collagens, and fibronectins. Reactome-based functional pathway analyses revealed that many of the ECM proteins are involved in extracellular matrix interactions required for cancer cell growth and proliferation. TP-472 treatment also upregulated several pro-apoptotic genes that can inhibit melanoma growth. Collectively, our results identify BRD7/9 inhibitor TP-472 as a potentially useful therapeutic agent for melanoma therapy.