CDK4/6 与 mTORC1 双重抑制在易位型肾细胞癌中的协同临床前活性

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.