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MEK inhibitor sensitivity in BRAF fusion-driven prostate cancer

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Abstract

Purpose

The identification of subpopulations harboring druggable targets has become a major step forward in the subclassification of solid tumors into small groups suitable for specific therapies. BRAF fusions represent a paradigm of uncommon and targetable oncogenic events and have been widely correlated to the development of specific malignancies. However, they are only present in a limited frequency across most common tumor types. At this regard, we performed a genomic screening aimed to identifying rare variants associated to advanced prostate cancer development.

Methods

Tumoral tissue genomic screening of 41 patients develo** advanced prostate cancer was performed at our center as part of the GETHI XX study. The project, sponsored by the Spanish Collaborative Group in Rare Cancers (GETHI), aims to analyze the molecular background of rare tumors and to discover unfrequent molecular variants in common tumors.

Results

Here we present the clinical outcome and an in-deep molecular analysis performed in a case harboring a SND1-BRAF fusion gene. The identification of such rearrangement in a patient refractory to standard therapies led to the administration of trametinib (MEK inhibitor). Despite unsensitive to standard therapies, the patient achieved a dramatic response to trametinib. A comprehensive study of the tumor demonstrated this event to be a trunk alteration with higher expression of MEK in areas of tumor invasion.

Conclusions

Our study describes the patient-driven discovery of the first BRAF fusion-driven prostate cancer effectively treated with trametinib. Consequently, MAPK pathway activation could define a new subtype of prostate cancer susceptible to a tailored management.

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Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

Author notes

  1. María Dolores Fenor de la Maza and Sergio Ruiz-Llorente have equally contributed to the article.

Authors and Affiliations

  1. Laboratory of Innovation in Oncology, HM CIOCC MADRID (Centro Integral Oncológico Clara Campal), Hospital Universitario HM Sanchinarro, HM Hospitales, Madrid, Spain

    María Dolores Fenor, Sergio Ruiz-Llorente, Juan Francisco Rodríguez-Moreno, Elena Sevillano-Fernández, Paloma Navarro, Mónica Yagüe-Fernández, Sandra Amarilla-Quintana, Arantzazu Barquín & Jesús García-Donas

  2. Department of Genitourinary and Gynecological Tumors, Hospital Universitario HM Sanchinarro, HM Hospitales, Madrid, Spain

    María Dolores Fenor, Sergio Ruiz-Llorente, Juan Francisco Rodríguez-Moreno, Elena Sevillano-Fernández, Paloma Navarro, Mónica Yagüe-Fernández, Sandra Amarilla-Quintana, Arantzazu Barquín & Jesús García-Donas

  3. Institute of Applied Molecular Medicine (IMMA), Department of Basic Medical Sciences, Facultad de Medicina, Universidad San Pablo CEU, CEU Universities, Urbanización Montepríncipe, Monteprincipe Avenue, 28668, Madrid, Spain

    Sergio Ruiz-Llorente, Juan Francisco Rodríguez-Moreno, Elena Sevillano-Fernández, Paloma Navarro, Mónica Yagüe-Fernández, Sandra Amarilla-Quintana, Arantzazu Barquín & Jesús García-Donas

  4. Histopathology Core Unit, Spanish National Cancer Center (CNIO), Madrid, Spain

    Eduardo Caleiras

  5. Medical Oncology Department, Campo Grande Hospital, Valladolid, Spain

    Juan Carlos Torrego

Authors
  1. María Dolores Fenor
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  2. Sergio Ruiz-Llorente
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  3. Juan Francisco Rodríguez-Moreno
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  4. Eduardo Caleiras
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  5. Juan Carlos Torrego
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  6. Elena Sevillano-Fernández
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  7. Paloma Navarro
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  8. Mónica Yagüe-Fernández
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  9. Sandra Amarilla-Quintana
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  10. Arantzazu Barquín
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  11. Jesús García-Donas
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Corresponding author

Correspondence to Jesús García-Donas.

Ethics declarations

Conflict of interest

M. Fenor de la Maza: Travel, accommodations, expenses; ROCHE.; Travel, accommodations, expenses; BMS.; Travel, accommodations, expenses; MSD.; Travel, accommodations, expenses; PIERRE-FABRE.; Travel, accommodations, expenses; BAYERN.; Travel, accommodations, expenses; PFIZER.; Travel, accommodations, expenses; JANSEN.; Travel, accommodations, expenses; NOVARTIS.; Travel, accommodations, expenses; MERK.; Travel, accommodations, expenses; ASTRA-ZENECA. S. Ruiz: Expenses; ROCHE. S. Ruiz: Expenses; ROCHE. J. Rodríguez Moreno:; Speaker honoraria, Travel, accommodations, expenses, Corporate-sponsored research; BMS.; Speaker honoraria, Travel, accommodations, expenses, Corporatesponsored research; Amgen.; Speaker honoraria, Travel, accommodations, expenses, Corporate-sponsored research; Bioclin.; Speaker honoraria, Travel, accommodations, expenses, Corporate-sponsored research; Roche.; Speaker honoraria, Travel, accommodations, expenses, Corporate-sponsored research; Novartis.; Speaker honoraria, Travel, accommodations, expenses, Corporate-sponsored research; MSD.; Speaker honoraria, Travel, accommodations, expenses, Corporate-sponsored research; Jansen.; Speaker honoraria, Travel, accommodations, expenses, Corporate-sponsored research; Pfizer.; Speaker honoraria, Travel, accommodations, expenses, Corporate-sponsored research; Astra-Zeneca.; Speaker honoraria, Travel, accommodations, expenses, Corporate-sponsored research; MERK. E. Caleiras: None. J. Torrego: None. E. Sevillano: ROCHE.; PIERRE FABRE.; BMS.; MSD.; ASTRA ZENECA.; PFIZER. P. Navarro: Travel, accommodations, expenses; ROCHE. M. Yagüe: None. S. Amarilla: Expenses; ROCHE. A. Barquin: ROCHE.; PIERRE FABRE.; BMS.; MSD.; ASTRA ZENECA.; PFIZER. J. García Donas: Novartis.; Pfizer.; Bristol Meiers Squibb.; Roche.; Piere Fabre.; Janssen Cilag.; Astellas.

Ethical approval and Informed consent

The study was approved by the ethics committee at the HM Hospital Sanchinarro (Madrid; Spain) and patient provided written consent.

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Fenor, M.D., Ruiz-Llorente, S., Rodríguez-Moreno, J.F. et al. MEK inhibitor sensitivity in BRAF fusion-driven prostate cancer. Clin Transl Oncol 24, 2432–2440 (2022). https://doi.org/10.1007/s12094-022-02916-6

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