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PURPOSE: Translocation renal cell carcinoma (tRCC) is a rare and aggressive subtype of kidney cancer driven by an oncogenic fusion involving a transcription factor in the gene family, most commonly . Treatment of tRCC currently lacks a clear standard of care, underscoring the pressing need to nominate new therapeutic targets with mechanistic rationale in this cancer.EXPERIMENTAL DESIGN: In this study, we applied integrative genomic approaches to identify activation of the cyclin-dependent kinase 4/6 (CDK4/6) and mammalian target of rapamycin complex 1 (mTORC1) pathways in tRCC. We tested the activity of CDK4/6 inhibitors (CDK4/6i), alone or in combination with mTORC1-selective inhibition, using and models of tRCC.RESULTS: tRCC tumors displayed multiple genomic and transcriptional features associated with activation of the CDK4/6 and mTORC1 signaling pathways. Genetic or pharmacologic inhibition of CDK4/6 suppressed tRCC cell growth and induced cell cycle arrest but was not cytotoxic, with rapid cell regrowth observed after drug withdrawal. The mTORC1-selective inhibitor, RMC-5552, potently reduced translation of Cyclin D1, which complexes with CDK4/6 proteins to regulate G1-S cell cycle progression. Combined treatment with the CDK4/6 inhibitor, palbociclib, and RMC-5552 resulted in synergistic suppression of tRCC cell viability and increased markers of apoptosis . The combination of palbociclib and RMC-5552 in a tRCC xenograft model showed greater efficacy than either single agent while also being well-tolerated.CONCLUSIONS: Our study indicates the therapeutic potential of combined CDK4/6 and mTORC1 inhibition in tRCC, providing the rationale for further clinical evaluation of this strategy.