# Molecular mechanisms and therapeutic targeting of activated NRF2 signaling in MiT/TFE translocation renal cell carcinoma

> **NIH NIH R01** · DANA-FARBER CANCER INST · 2024 · $464,974

## Abstract

PROJECT SUMMARY
Renal cell carcinoma (RCC) is one of the top ten most common cancers worldwide and is comprised of multiple
distinct histologies. One particularly aggressive subtype of RCC is translocation renal cell carcinoma (tRCC), a
devastating and aggressive neoplasm that is defined by a gene fusion involving a transcription factor in the
MiT/TFE gene family, most commonly TFE3. Currently, there are no approved therapeutic agents that are
specifically targeted to the biology of tRCC. In addition, we have an incomplete understanding of how TFE3
fusions drive this cancer, which represents a major unmet medical need. We recently applied genomic discovery
approaches to identify genes and/or pathways that may represent novel therapeutic targets in tRCC. These
studies revealed activation of the nuclear factor erythroid 2–related factor 2 (NRF2) pathway – a master regulator
of a cell’s response to oxidative stress – to be a defining feature of tRCC. Interestingly, in tRCC, NRF2 activation
occurs without the activating somatic alterations in this pathway that are usually found in other cancers, such as
amplification of NFE2L2 (the gene encoding NRF2) or inactivation of KEAP1 (a negative regulator of NRF2),
suggesting a novel mode of NRF2 regulation in tRCC. In this project, we will explore the molecular mechanisms
by which NRF2 signaling is activated in tRCC and will also establish the therapeutic potential of targeting the
NRF2 pathway in this cancer. In Aim 1, we will dissect the molecular mechanisms by which TFE3 fusions regulate
NRF2 signaling in tRCC. We will test the hypothesis that TFE3 fusions and NRF2 coordinately regulate the
expression and function of critical antioxidant genes. We will also use unbiased functional genetic and chemical
proteomic approaches to identify critical redox-sensitive effectors of TFE3 fusions in tRCC. In Aim 2, we will test
the functional consequences and therapeutic potential of NRF2 pathway inhibition in tRCC. We will assess
protein markers of NRF2 pathway activation in tRCC tumor tissue. We will then use both genetic and small
molecule approaches to determine whether NRF2 inhibition represents a dependency in tRCC cells both in vitro
and in vivo. This project leverages innovative biochemical and functional genetic approaches to clarify the basic
mechanisms by which NRF2 signaling is regulated by TFE3 fusions. More broadly, these studies may have
implications for understanding how the NRF2 pathway is regulated in other cancers. This project also seeks to
credential the NRF2 pathway as a therapeutic target in tRCC, thereby advancing a mechanism-driven
therapeutic hypothesis with the potential to improve outcomes in a cancer that represents an unmet medical
need with no established standard of care.

## Key facts

- **NIH application ID:** 10881882
- **Project number:** 5R01CA279044-02
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Srinivas Raghavan Viswanathan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $464,974
- **Award type:** 5
- **Project period:** 2023-08-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10881882

## Citation

> US National Institutes of Health, RePORTER application 10881882, Molecular mechanisms and therapeutic targeting of activated NRF2 signaling in MiT/TFE translocation renal cell carcinoma (5R01CA279044-02). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10881882. Licensed CC0.

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