Targeting CDK4/6 and mTORC1 in Translocation Renal Cell Carcinoma

Translocation renal cell carcinoma (tRCC) represents a rare and historically underserved subtype of kidney cancer, primarily characterized by gene fusions involving the MiT family, specifically TFE3 or TFEB. Due to its scarcity and aggressive clinical course, tRCC remains a significant therapeutic challenge and currently lacks a dedicated FDA-approved standard of care. Consequently, clinicians often rely on off-label strategies derived from more common renal malignancies, which frequently yield suboptimal long-term results for this distinct patient population.

Contextualized by a presentation she gave at the 2026 American Association for Cancer Research (AACR) Annual Meeting, Shikha Gupta, PhD, spoke with CancerNetwork® about pivotal data that may offer a more tailored path forward in this space. Her research uncovered a unique co-activation of the CDK4/6 and mTORC1 signaling pathways in tRCC models. By pairing the established CDK4/6 inhibitor palbociclib (Ibrance) with the selective mTORC1 inhibitor RMC-5552, Gupta’s team achieved significant synergistic tumor regression in preclinical studies, suggesting a potential new avenue for precision medicine.

Gupta further delved into the mechanistic rationale of this dual-inhibition strategy, explored the potential for this combination to serve as a frontline regimen, and addressed the monitoring of adverse effects (AEs) as the work transitions toward human trials. These findings may signal a promising shift toward biology-driven therapies for patients navigating this rare diagnosis.

Gupta is a postdoctoral research fellow at Dana-Farber Cancer Institute.

CancerNetwork: Can you provide a brief background and overview of your presentation at the conference?

Gupta: Through this work, we studied the biology of translocation kidney cancer, which some in the community may know is a rare subtype of kidney cancer that currently lacks a standard of care. In this work, we showed that there is a unique activation of both CDK 4/6 and mTORC1 signaling in tRCC. We investigated the functional and mechanistic impact of individually targeting these pathways and developed a novel combination strategy where we proposed using the CDK4/6 inhibitor palbociclib in combination with the selective mTORC1 inhibitor RMC-5552. We see that this combination leads to a stable tumor regression in our models, and we believe these findings could inform the design of future clinical trials specifically tailored for tRCC biology.

The abstract noted that the combination resulted in a synergistic suppression of cell viability. Mechanistically, does the mTORC1 inhibitor primarily work by downregulating cyclin D1 to sensitize the cells to CDK4/6 inhibition, or are there additional non-canonical pathways being hit that prevent the rapid cell regrowth observed with palbociclib monotherapy?

mTORC1 signaling activates cyclin D1, which is well known in literature, via its downstream effector 4EBP1 by phosphorylating it. Inhibition of mTORC1 reduces cyclin D1 activity, as we showed in this study, which makes this combination more effective. With that said, we also believe that there are additional non-canonical mechanisms that may contribute to the enhanced and more durable response, and those are currently under investigation.

Given that tRCC is a heterogeneous group defined by different MiT/TFE gene fusions, did your genomic profiling identify specific fusion partners or co-occurring mutations that rendered certain models more sensitive to this combination?

This is an ongoing challenge in the field. In other cancer models, such as breast cancer, loss of p16 or CDKN2A activity has been shown to be associated with potentially enhanced sensitivity to CDK4/6 inhibitors, but multiple studies have shown that p16 status alone is not a reliable biomarker of response or resistance to these drugs. In terms of the fusion partners, we have not seen any specific fusion partner being more sensitive towards this combination. Having said that, it is also a rare subtype, so the genomic cohorts we have studied are still small. It is challenging to draw definitive conclusions at this stage.

Both CDK 4/6 inhibition and mTOR inhibitors are associated with distinct toxicity profiles––specifically myelosuppression and mucositis or hyperglycemia, respectively. What specific AEs should clinicians prioritize monitoring for if this combination moves into phase 1 human trials?

[This] can be best addressed in a clinical setting. Based on literature and insights from previous trials where these pathways have been targeted across different tumor models, my understanding is to look for fatigue, neutropenia, or GI tract-related issues.

Since the current off-label standard for tRCC often involves VEGFR-TKIs or immune checkpoint inhibitors (ICIs), do you have data or a hypothesis on how the CDK4/6-mTORC1 axis interacts with the angiogenic or immune landscape of tRCC? Would you see this combination potentially replacing frontline therapy or serving as a salvage regimen after ICI failure?

CDK4/6 inhibitors have been shown to have anti-angiogenic activity as well as pro-immunogenic activity, which was mostly studied in breast cancer models. We have not studied the impact in tRCC, specifically. Regarding frontline therapy, given that translocation kidney cancer currently lacks any well-defined standard of care, this combination could have potential as a frontline therapy. Based on prior literature suggesting CDK4/6 inhibitors are pro-immunogenic, this may also enhance responses to ICIs, but that is still an area that needs to be further explored.

In the abstract, you mentioned that drug withdrawal led to rapid cell regrowth in vitro. In your in vivo models, did the combination therapy achieve sustained complete remissions, or did you observe the eventual emergence of acquired resistance? If resistance occurred, what were the preliminary escape mechanisms?

The combination therapy did achieve sustained remission in both in vitro and in vivo models, but we saw resistance emerge eventually. We are trying to understand those mechanisms contributing to resistance through ongoing functional and mechanistic studies. We believe that some of these mechanisms may be associated with the tumor microenvironment, but it is still at a very early stage to be able to comment further.

Are there any other research or presentations you would like to highlight from the conference?

It is hard to highlight specific presentations given that AACR is a large and diverse conference. However, I am particularly interested in sessions focused on defining the rationale for combination therapies, especially ones targeting CDK4/6 signaling.

Is there anything else you would like to discuss?

I would add that we are excited about the potential of this work to move into the clinic in the future and ultimately benefit patients in need. We have already received strong interest from multiple groups across the US and internationally, so we are looking forward to expanding in this area.

Reference

Gupta S, Khanna P, Saad E, et al. Synergistic preclinical activity of dual CDK4/6 and mTORC1 inhibition in translocation renal cell carcinoma. Presented at the 2026 American Association for Cancer Research Annual Meeting; April 17-22, 2026; San Diego, CA. Abstract 3160.