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. 2025 May;27(5):2241-2255.
doi: 10.1007/s12094-024-03652-9. Epub 2024 Oct 4.

Retrospective study assessing the role of the androgen receptor in clear cell renal cell cancer patients treated with VEGFR inhibitors in monotherapy

Lucia Osorio  1   2 , Tatiana P Grazioso  2   3   4 , Guillermo de Velasco  5 , Olatz Etxaniz  6 , Jose Luis Pérez-Gracia  7 , Álvaro Pinto  8 , Ignacio Durán  9 , Enrique Grande  10 , Pablo Borrega Garcia  11 , Martín Lázaro  12 , Laura Rodriguez  13 , Maria Laura Villalobos  14 , Lourdes García  15 , Andrés Cuellar  16 , María Pilar Solís-Hernández  17 , Cristina Pernaut  18 , Juan Francisco Rodríguez-Moreno  2   3   4 , Cristina Rodriguez-Antona  19   20 , Jesús García-Donas  21   22   23
Affiliations

Retrospective study assessing the role of the androgen receptor in clear cell renal cell cancer patients treated with VEGFR inhibitors in monotherapy

Lucia Osorio et al. Clin Transl Oncol. 2025 May.

Abstract

Background and purpose: Despite that incorporating antiangiogenic in combination with immune-checkpoint inhibitors as the standard first-line treatment for advanced clear cell renal cell cancer (ccRCC) yields promising outcomes, these regimens often lead to significant toxicity. However, a subgroup of patients has shown responsiveness to VEGFR tyrosine-kinase inhibitors (TKIs) in monotherapy, leading to the question of whether employing combination therapies can significantly enhance overall survival in all patients over monotherapy. Thus, we aim to identify gene expression signatures that can predict TKI response within subpopulations that might benefit from single-agent therapies, to minimize unnecessary exposure to combination therapies and their associated toxicities, as well as to discover new potential therapeutic targets to improve ccRCC treatment. Based on prior data, the androgen receptor (AR) might meet both conditions.

Patients and methods: We evaluated the association between AR expression, assessed through NanoString® technology-derived mRNA counts, and the clinical outcomes of 98 ccRCC patients treated with first-line antiangiogenics and determined its association with other genes implicated in ccRCC tumorigenesis.

Results: Higher AR-expression correlates significantly with better prognosis and survival based on the MSKCC risk score, and longer PFS. Furthermore, we have identified a gene set signature associated with AR-overexpression and several genes involved in angiogenesis and transcriptional targets of the hypoxia-inducible factor, a cornerstone of ccRCC.

Conclusions: AR-overexpression and its association with other genes could favor a transcriptomic signature set to aid in identifying patients suitable for TKI in monotherapy, rather than aggressive combinations, enhancing thus, precision and personalized therapeutic decisions.

Keywords: Advanced clear cell renal cell cancer (ccRCC); Androgen receptor (AR); Antiangiogenics; Tyrosine kinase inhibitors (TKIs).

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Conflict of interest statement

Declarations. Informed consent: Written informed consent was obtained from all subjects involved in the study. Institutional review board statement: The study was conducted in accordance with the Declaration of Helsinki, and approved by the Ethics Committee “Comité Ético de Investigación con medicamentos HM Hospitales_CEIm” (protocol code “CEIC-Grupo HM: 18.10.1311-GHM”) on the 17 of Octubre of 2013. Conflicts of interest: The authors have no competing interests to declare that are relevant to the content of this article. All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript. The authors have no financial or proprietary interests in any material discussed in this article.

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