Abstract 3160: Synergistic preclinical activity of dual CDK4/6 and mTORC1 inhibition in translocation renal cell carcinoma

Abstract Background: Translocation renal cell carcinoma (tRCC) is an aggressive subtype of RCC driven by a gene fusion involving a transcription factor in the MiT/TFE gene family, most commonly TFE3. There are currently no approved therapeutic agents specific to tRCC and this subtype of kidney cancer represents a major unmet medical need. Methods: We utilized integrative genomic approaches associated with activation of the cyclin- dependent kinase 4/6 (CDK4/6) and mammalian target of rapamycin complex 1 (mTORC1) signaling in tRCC. We tested the activity of CDK4/6 inhibitors (CDK4/6i), alone or in combination with mTORC1-selective inhibition, using in vitro and in vivo models of tRCC. Results: Our work shows that tRCC tumors harbor multiple genomic and transcriptional features associated with activation of the CDK4/6 and mTORC1 signaling pathways. Pharmacological inhibition of CDK4/6 activity using palbociclib or abemaciclib, causes cell cycle arrest which was also recapitulated upon genetic knockout of CDK4/6 using CRISPR-Cas9. This was further accompanied by impaired cell growth in long-term culture in presence of palbociclib with a rapid cell regrowth observed upon drug withdrawal. CDK4/6 proteins regulate G1-S cell cycle progression by combining with CyclinD1, the expression of which is significantly reduced upon treatment with mTORC1-selective inhibitor, RMC-5552. Combined treatment with the CDK4/6 inhibitor, palbociclib, and RMC-5552 resulted in synergistic suppression of tRCC cell viability and increased markers of apoptosis in vitro. 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 work suggests that combined inhibition of CDK4/6 and mTORC1 activity has therapeutic potential in tRCC. This work may offer rationale for molecularly directed therapies in tRCC, which currently lacks any standard of care. Citation Format: Shikha Gupta, Prateek Khanna, Eddy Saad, Renée Maria Saliby, Shatha AbuHammad, Jiao Li, Bingchen Li, Prathyusha Konda, Usman Ali Ahmed, Ananthan Sadagopan, Qingru Xu, Ziad El Bakouny, Wenxin Xu, Ramaprasad Srinivasan, Toni K. Choueiri, Srinivas R. Viswanathan. Synergistic preclinical activity of dual CDK4/6 and mTORC1 inhibition in translocation renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3160.