# Strategies to Disrupt Oncogenic Transcription in RCC Tumors

> **NIH NIH R01** · GEORGETOWN UNIVERSITY · 2024 · $339,008

## Abstract

• 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.

## Key facts

- **NIH application ID:** 10873183
- **Project number:** 5R01CA263630-04
- **Recipient organization:** GEORGETOWN UNIVERSITY
- **Principal Investigator:** Chunling Yi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $339,008
- **Award type:** 5
- **Project period:** 2021-07-05 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10873183

## Citation

> US National Institutes of Health, RePORTER application 10873183, Strategies to Disrupt Oncogenic Transcription in RCC Tumors (5R01CA263630-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10873183. Licensed CC0.

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