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.
Highlights
Melanoma is the deadliest form of skin cancer, accounting for 85% of all skin cancer–related deaths [1]
We performed mRNA sequencing analyses to elucidate the mechanism by which TP-472 inhibits the growth of melanoma cells. These analyses revealed that TP-472 treatment leads to reduced extracellular matrix (ECM)-mediated oncogenic signaling and increased apoptosis that promotes inhibition of melanoma growth
To determine if targeting these epigenetic regulators will have an effect on BRAFmutant melanoma growth, we conducted a chemical genetics screen using the Structural
Summary
Melanoma is the deadliest form of skin cancer, accounting for 85% of all skin cancer–related deaths [1]. Previous genome-scale sequencing studies have identified mutations in a number of genes involved in the initiation and progression of melanoma, including BRAF (50%), NRAS (20–30%), neurofibromin 1 (NF1) (10–15%), and cyclin-dependent kinase inhibitor 2A (CDKN2A) (20–40%) [3]. Current therapies for advanced melanoma include several clinically approved BRAF inhibitors (BRAFi; e.g., vemurafenib, dabrafenib) in combination with MEK inhibitors (MEKi; e.g., trametinib) [4,5]. BRAFi/MEKi combination treatments produce impressive initial clinical responses in a subset of BRAFmutant advanced melanoma patients, resistance to treatment rapidly emerges within a few months, rendering the therapy ineffective [6,7]. Advanced melanoma patients can develop either intrinsic or acquired resistance to various immunotherapies following the initial response [8]. Additional new therapeutic approaches are necessary for treating advanced melanoma
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