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

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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.