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Volume 27
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10.3390/ijms27010476
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Identification of a Muscle-Invasive Bladder Carcinoma Molecular Subtype of Poor Responders to Neoadjuvant Chemotherapy and High Expression of Targetable Biomarkers

by
Lucía Trilla-Fuertes
1,
Jorge Pedregosa-Barbas
2,
Eugenia García-Fernández
3,
Francisco Zambrana
4,
Imanol Martínez-Salas
5,
Pablo Gajate
6,
Fernando Becerril-Gómez
1,
Pedro Lalanda-Delgado
1,
Antje Dittmann
7,
Rocío López-Vacas
1,
Laura Kunz
7,
Gustavo Rubio
4,
Sandra Nieto-Torrero
8,
Ana Pertejo
2,
Pilar González-Peramato
3,
Juan Ángel Fresno Vara
1,9,
Angelo Gámez-Pozo
1,9,*,† and
Álvaro Pinto-Marín
2,*,†
1
Molecular Oncology Lab, INGEMM, La Paz University Hospital-IdiPAZ, Paseo de la Castellana 261, 28046 Madrid, Spain
2
Medical Oncology Service, La Paz University Hospital-IdiPAZ, Paseo de la Castellana 261, 28046 Madrid, Spain
3
Department of Pathology, La Paz University Hospital-IdiPAZ, UAM, 28046 Madrid, Spain
4
Medical Oncology Department, Infanta Sofía University Hospital, Madrid, Spain
5
Medical Oncology Department, IIS-FJD, University Hospital Fundación Jiménez Díaz, Madrid, Spain
6
Medical Oncology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain
7
Functional Genomics Center Zurich, University of Zurich/ETH Zurich, Zurich, Switzerland
8
IdiPAZ Biobank, La Paz University Hospital-IdiPAZ, Madrid, Spain
9
Biomedical Research Networking Center on Oncology-CIBERONC, ISCIII, Madrid, Spain
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2026, 27(1), 476; https://doi.org/10.3390/ijms27010476
Submission received: 18 November 2025 / Revised: 19 December 2025 / Accepted: 31 December 2025 / Published: 2 January 2026
(This article belongs to the Section Molecular Oncology)
Versions Notes

Abstract

Neoadjuvant chemotherapy (NACT) is the standard treatment for muscle-invasive bladder carcinoma (MIBC), but its efficacy varies significantly among patients. The aim of this study is the identification of biomarkers and biological processes related to the response to neoadjuvant chemotherapy (NACT) in muscle-invasive bladder carcinoma (MIBC). Fifty-eight transurethral resection (TURBT) samples and thirty cystectomy samples from NACT non-responders were analyzed using mass spectrometry. Samples were classified with sparse k-means and consensus clustering. Protein networks were built using probabilistic graphical models, grouped into functional nodes, and analyzed for activity differences. Gene set enrichment analysis was applied to identify resistance mechanisms, and results were validated using The Cancer Genome Atlas (TCGA) cohort. Proteomic analysis revealed two independent classifications in TURBT samples. The first (Layer1) divided tumors into three groups, including one NACT non-responder subtype not aligned with traditional luminal or basal classifications but characterized by high expression of targetable markers NECTIN4 and Her2. The second (Layer3) separated luminal-papillary tumors from luminal-infiltrated/luminal and basal tumors. While Layer3 groups did not differ in NACT response, they showed distinct disease-free survival outcomes. Importantly, complete response to NACT was linked to improved survival in luminal subgroups but not in basal tumors, suggesting subtype-specific prognostic implications. Finally, analysis of cystectomy samples identified unique mechanisms of resistance for each subgroup, suggesting tailored therapeutic approaches. Two classification systems were defined as follows: one identified a proteomics-based non-responder group with actionable targets, and the other linked tumor subtype to prognosis. Distinct resistance mechanisms suggest opportunities for subtype-specific therapies, supporting improved management and treatment development for MIBC patients.
Keywords: muscle-invasive bladder cancer; proteomics subtype; response to neoadjuvant chemotherapy; targetable biomarkers muscle-invasive bladder cancer; proteomics subtype; response to neoadjuvant chemotherapy; targetable biomarkers

Share and Cite

MDPI and ACS Style

Trilla-Fuertes, L.; Pedregosa-Barbas, J.; García-Fernández, E.; Zambrana, F.; Martínez-Salas, I.; Gajate, P.; Becerril-Gómez, F.; Lalanda-Delgado, P.; Dittmann, A.; López-Vacas, R.; et al. Identification of a Muscle-Invasive Bladder Carcinoma Molecular Subtype of Poor Responders to Neoadjuvant Chemotherapy and High Expression of Targetable Biomarkers. Int. J. Mol. Sci. 2026, 27, 476. https://doi.org/10.3390/ijms27010476

AMA Style

Trilla-Fuertes L, Pedregosa-Barbas J, García-Fernández E, Zambrana F, Martínez-Salas I, Gajate P, Becerril-Gómez F, Lalanda-Delgado P, Dittmann A, López-Vacas R, et al. Identification of a Muscle-Invasive Bladder Carcinoma Molecular Subtype of Poor Responders to Neoadjuvant Chemotherapy and High Expression of Targetable Biomarkers. International Journal of Molecular Sciences. 2026; 27(1):476. https://doi.org/10.3390/ijms27010476

Chicago/Turabian Style

Trilla-Fuertes, Lucía, Jorge Pedregosa-Barbas, Eugenia García-Fernández, Francisco Zambrana, Imanol Martínez-Salas, Pablo Gajate, Fernando Becerril-Gómez, Pedro Lalanda-Delgado, Antje Dittmann, Rocío López-Vacas, and et al. 2026. "Identification of a Muscle-Invasive Bladder Carcinoma Molecular Subtype of Poor Responders to Neoadjuvant Chemotherapy and High Expression of Targetable Biomarkers" International Journal of Molecular Sciences 27, no. 1: 476. https://doi.org/10.3390/ijms27010476

APA Style

Trilla-Fuertes, L., Pedregosa-Barbas, J., García-Fernández, E., Zambrana, F., Martínez-Salas, I., Gajate, P., Becerril-Gómez, F., Lalanda-Delgado, P., Dittmann, A., López-Vacas, R., Kunz, L., Rubio, G., Nieto-Torrero, S., Pertejo, A., González-Peramato, P., Fresno Vara, J. Á., Gámez-Pozo, A., & Pinto-Marín, Á. (2026). Identification of a Muscle-Invasive Bladder Carcinoma Molecular Subtype of Poor Responders to Neoadjuvant Chemotherapy and High Expression of Targetable Biomarkers. International Journal of Molecular Sciences, 27(1), 476. https://doi.org/10.3390/ijms27010476

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