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Updated: Aug 31, 2025
Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
Published on: July 17, 2019
MEK inhibitor sensitivity in BRAF fusion-driven prostate cancer
María Dolores Fenor1,2, Sergio Ruiz-Llorente1,2,3, Juan Francisco Rodríguez-Moreno1,2,3
1Laboratory of Innovation in Oncology, HM CIOCC MADRID (Centro Integral Oncológico Clara Campal), Hospital Universitario HM Sanchinarro, HM Hospitales, Madrid, Spain.
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 developing 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.
Insights
We identified a BRAF fusion in advanced prostate cancer, a rare event. This patient responded dramatically to trametinib, a MEK inhibitor, suggesting a new therapeutic strategy for this specific cancer subtype.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Targetable molecular alterations are crucial for classifying solid tumors for personalized therapies.
- BRAF fusions are uncommon but significant oncogenic events in various malignancies.
- Identifying rare variants in common cancers like prostate cancer is essential for advancing treatment.
Purpose of the Study:
- To perform genomic screening to identify rare variants associated with advanced prostate cancer.
- To investigate the molecular background of rare tumors and discover infrequent molecular variants in common tumors.
Main Methods:
- Genomic screening of tumoral tissue from 41 patients with advanced prostate cancer.
- Analysis conducted as part of the GETHI XX study, focusing on rare and infrequent molecular variants.
Main Results:
- A case of advanced prostate cancer with a SND1-BRAF fusion gene was identified.
- The patient, refractory to standard therapies, showed a dramatic response to trametinib (MEK inhibitor).
- The BRAF fusion was confirmed as a trunk alteration with increased MEK expression in invasive areas.
Conclusions:
- This study reports the first case of BRAF fusion-driven prostate cancer successfully treated with trametinib.
- MAPK pathway activation may define a novel, targetable subtype of prostate cancer.
- Patient-driven discovery highlights the potential of targeted therapies for rare oncogenic events.
