ARNT Expression Patterns Hold Promise for HIF-1β Inhibition in RCC Subtypes

Investigating novel molecular targets across renal cell carcinoma (RCC) histologies remains critical to expanding precision oncology options. At the 2026 Kidney Cancer Research Summit (KCRS), Yu-Wei Chen, MD, MS, presented research analyzing ARNT (HIF-1β) expression patterns across approximately 4000 clear cell and non–clear cell RCC tumors utilizing comprehensive DNA and RNA sequencing.

Driven by the early-stage clinical evaluation of NEO-811, a selective HIF-1β inhibitor, the analysis demonstrated that ARNT expression is broadly preserved across tumor types, showing the highest levels in clear cell RCC followed by papillary, medullary, and chromophobe histologies. Crucially, expression levels remained stable between primary and metastatic sites, with no significant variance observed across racial or ethnic cohorts. While ARNT did not demonstrate prognostic or predictive biomarker utility in this cohort, its widespread, consistent expression supports evaluating HIF-1β inhibition beyond clear cell histologies into broader non–clear cell RCC populations.

Chen is an assistant professor of medicine specializing in genitourinary oncology at the University of California San Diego.

Transcript:

CancerNetwork: At KCRS 2026, you presented research dissecting ARNT expression patterns in RCC and their association with patient outcomes. What are the key translational findings from this analysis, and how might ARNT expression serve as a predictive or prognostic biomarker to refine treatment selection?

Chen: We [profiled] about 4000 RCC tumors with DNA and RNA sequencing, focusing on ARNT expression. ARNT, also known as HIF-1β, dimerizes with HIF-2α, and the main reason we conducted this analysis is that there is currently a phase 1 study investigating NEO-811, a HIF-1β inhibitor. We wanted to see how ARNT expression looks across RCC tumors in both clear cell and non-clear cell [histologies].

We found that ARNT expression was quite consistent across RCC histologies. We [saw] relatively higher expression in clear cell RCC compared with papillary [disease], followed by medullary RCC and chromophobe. We also saw consistent ARNT expression across primary RCC tumors as well as metastatic tumors, and there were no differences by racial or ethnic subgroup. Overall, the positive finding from this study is that we see consistent, preserved ARNT expression, so if the phase 1 study is able to move forward, we may have the opportunity to investigate ARNT inhibition not only in clear cell RCC but also to see what the efficacy looks like in non–clear cell RCC. In terms of prognostic or predictive value, we did not see ARNT expression serve as a biomarker in our analysis at this point.

Reference

Chen YW, Nazari SS, Elliott A, et al. Dissecting ARNT (HIF-1β) expression patterns in renal cell carcinoma and associations with outcomes. Presented at: 2026 Kidney Cancer Research Summit (KCRS26); July 23-24, 2026; Boston, MA.