Abstract PR017: Exploiting CDK4/6-mTORC1 dependency reveals synergistic therapeutic potential in translocation renal cell carcinoma

Abstract Background- Translocation renal cell carcinoma (tRCC) is a highly aggressive form of RCC characterized by gene fusions involving MiT/TFE family transcription factors, most commonly TFE3. There are no approved therapies specifically tailored for tRCC, and this subtype remains a critical unmet clinical challenge. Methods- We used integrative genomic profiling to define pathway dependencies in tRCC, with a particular focus on cyclin-dependent kinase 4/6 (CDK4/6) and mammalian target of rapamycin complex 1 (mTORC1) signaling. The functional consequences of CDK4/6 inhibition, alone or paired with selective mTORC1 blockade, were evaluated in vitro and in vivo using tRCC models. Results- Our findings demonstrate that tRCC tumors exhibit extensive genomic and transcriptional evidence of heightened CDK4/6 and mTORC1 pathway activity. Pharmacologic CDK4/6 blockade with palbociclib or abemaciclib induced cell-cycle arrest, replicating the effects of CRISPR-Cas9 CDK4/6 deletion, and produced sustained reductions in proliferation, with rapid regrowth upon drug withdrawal. CDK4/6 promotes G1-S transition through CyclinD1, whose expression was markedly downregulated upon exposure to the mTORC1-selective inhibitor RMC-5552, revealing a mechanistic link between the pathways. Combined palbociclib and RMC-5552 treatment synergistically impaired tRCC viability and heightened apoptotic signaling in vitro. In xenograft models, the combination achieved superior tumor suppression over monotherapy with individual agents along with favorable tolerability. Conclusions- Our findings reveal a mechanistic dependency on coordinated CDK4/6 and mTORC1 signaling in tRCC and concurrent inhibition of CDK4/6 and mTORC1 represents a promising therapeutic approach for tRCC. This strategy supports the development of molecularly informed treatments for a cancer subtype that currently lacks a defined standard of care. Citation Format: Shikha Gupta, Prateek Khanna, Eddy Saad, Renee Maria. Saliby, Shatha AbuHammad, Jiao Li, Bingchen Li, Prathyusha Konda, Usman Ali. Ahmed, Ananthan Sadagopan, Qingru Xu, Ziad Bakouny, Wenxin Xu, Ramaprasad Srinivasan, Toni K. Choueiri, Srinivas Viswanathan. Exploiting CDK4/6-mTORC1 dependency reveals synergistic therapeutic potential in translocation renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Kidney Cancer Research: From Molecular Insights to Therapeutic Breakthroughs; 2026 Mar 13-16; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_2):Abstract nr PR017.