• PROJECT SUMMARY • Renal cell carcinoma (RCC) is the 8th most common form of adult cancer in the US. Despite recent improvement in treatment options, the majority of patients with metastatic RCC continue to succumb to this disease, resulting in over 100,000 deaths per year worldwide. Thus, it is important to identify novel therapeutic strategies to more effectively treat this deadly disease. Our preliminary studies suggest that YAP/TAZ function as master regulators of the core oncogenic transcriptional network across most subtypes of RCC and are required for maintaining the transcriptional and metabolic homeostasis of RCC tumors. The first major aim of our proposal is to determine the therapeutic efficacies and mechanisms of action of first-in-class YAP/TAZ inhibitors in patient-derived RCC tumor models. Besides in vivo efficacy studies, we will employ cutting-edge epigenomic techniques including Cut&Tag, omni-ATAC-seq and 3’-RNAseq to probe how genetic and pharmacological inhibition of YAP/TAZ affect the compositions and activities of the YAP/TAZ transcriptional complexes and the global epigenetic and transcriptional landscape in RCC tumors. Through these analyses, we will be able to gain critical insights into the molecular functions of YAP/TAZ in RCC tumors, but also reconstruct the core ensemble of the RCC oncogenic transcriptional network. The second major aim of this proposal is to develop mechanism-driven combination strategies to more effectively treat RCC tumors. Through high-throughput drug screening and extensive mechanistic studies, we recently identified MEK and BET inhibitors as two major classes of drugs that strongly synergize with genetic or pharmacological inhibition of YAP/TAZ to suppress oncogenic transcription and eliminate YAP/TAZ-addicted tumor cells in vitro and in vivo. Based on these results, we will investigate whether combining low doses of MEK or BET inhibitors with YAP/TAZ inhibitors could lead to durable tumor regression without increasing systematic toxicities in RCC PDX models. Furthermore, we will conduct functional genomic studies to elucidate how MEK and BET inhibitors amply the effects of YAP/TAZ inactivation, leading to the collapse of the RCC oncogenic transcriptional network. Finally, we will investigate how YAP/TAZ inhibitors affect the RCC tumor secretome and immune infiltrates and whether they could be used to overcome resistance to immune checkpoint inhibitors. Together, these studies will greatly enhance our understanding of the crosstalk and redundancies between the oncogenic pathways that govern the growth and survival of RCC cells, potentially yielding more effective combination strategies to overcome treatment resistance in RCC patients.