Targeting the CDK4/6 pathway in MiT/TFE-translocation renal cell carcinoma - 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 identified activation of the CDK4/6 pathway as a defining feature of tRCC. CDK4 and CDK6 are kinases that govern the G1 to S cell cycle transition and thereby promote cell proliferation. Importantly, drugs targeting these proteins are already FDA-approved for the treatment of certain breast cancers. In this project, we will test the mechanism-driven therapeutic hypothesis that targeting the CDK4/6 pathway, either alone or in combination with targeting of the PI3K/mTOR pathway, may be an effective therapeutic strategy in tRCC. In Aim 1, we will use genetic and pharmacologic approaches to test the sensitivity of tRCC cells to CDK4/6 inhibition in vitro and in vivo. We will also evaluate genomic, transcriptomic, and proteomic biomarkers of response to CDK4/6 inhibitors in tRCC tumor samples and preclinical models. In Aim 2, we will test the hypothesis that tRCC cells may be particularly sensitive to inhibition of the Cyclin D-CDK4/6 complex via a combination of CDK4/6 inhibition and PI3K/mTOR inhibition or mTORC1-selective inhibition, in both in vitro and in vivo models, due to a role for the latter pathway in stabilizing Cyclin D. This project aims to credential the CDK4/6 pathway in tRCC, which is an aggressive malignancy and an unmet medical need with no established standard of care. This project will clarify biomarkers of CDK4/6 pathway activation in tRCC and will also advance a therapeutic hypothesis using agents that are already approved or in late clinical development. Therefore, this work can be rapidly translated to design molecularly-inspired clinical trials of CDK4/6 monotherapy and/or combination therapy regimens for tRCC, which would have the potential to improve clinical outcomes for patients with this devastating cancer.
