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Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
Published on: July 17, 2019
Diverse BRAF Gene Fusions Confer Resistance to EGFR-Targeted Therapy via Differential Modulation of BRAF Activity
Christina Stangl1,2, Jasmin B Post3, Markus J van Roosmalen1,4
1Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht and Utrecht University, Utrecht, the Netherlands.
Abstract:
Fusion genes can be oncogenic drivers in a variety of cancer types and represent potential targets for targeted therapy. The BRAF gene is frequently involved in oncogenic gene fusions, with fusion frequencies of 0.2%-3% throughout different cancers. However, BRAF fusions rarely occur in the same gene configuration, potentially challenging personalized therapy design. In particular, the impact of the wide variety of fusion partners on the oncogenic role of BRAF during tumor growth and drug response is unknown. Here, we used patient-derived colorectal cancer organoids to functionally characterize and cross-compare BRAF fusions containing various partner genes (AGAP3, DLG1, and TRIM24) with respect to cellular behavior, downstream signaling activation, and response to targeted therapies. We demonstrate that 5' fusion partners mainly promote canonical oncogenic BRAF activity by replacing the auto-inhibitory N-terminal region. In addition, the 5' partner of BRAF fusions influences their subcellular localization and intracellular signaling capacity, revealing distinct subsets of affected signaling pathways and altered gene expression. Presence of the different BRAF fusions resulted in varying sensitivities to combinatorial inhibition of MEK and the EGF receptor family. However, all BRAF fusions conveyed resistance to targeted monotherapy against the EGF receptor family, suggesting that BRAF fusions should be screened alongside other MAPK pathway alterations to identify patients with metastatic colorectal cancer to exclude from anti-EGFR-targeted treatment. IMPLICATIONS: Although intracellular signaling and sensitivity to targeted therapies of BRAF fusion genes are influenced by their 5' fusion partner, we show that all investigated BRAF fusions confer resistance to clinically relevant EGFR inhibition.
Insights
BRAF fusion genes drive cancer, but their varied partners impact tumor growth and drug response. All BRAF fusions resist EGFR-targeted therapy, suggesting broader MAPK pathway screening for colorectal cancer patients.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Fusion genes are key drivers in various cancers, with BRAF fusions being significant oncogenic targets.
- The diverse configurations of BRAF fusions complicate personalized therapy design and understanding their oncogenic roles.
- The impact of varying fusion partners on BRAF's role in tumor progression and drug sensitivity remains largely unknown.
Purpose of the Study:
- To functionally characterize and compare BRAF fusions with different partner genes (AGAP3, DLG1, TRIM24) in colorectal cancer.
- To investigate how 5' fusion partners influence BRAF's oncogenic activity, subcellular localization, and downstream signaling.
- To assess the response of BRAF fusions to targeted therapies, including MEK and EGF receptor inhibitors.
Main Methods:
- Utilized patient-derived colorectal cancer organoids for functional analysis.
- Cross-compared BRAF fusions with partners AGAP3, DLG1, and TRIM24.
- Evaluated cellular behavior, downstream signaling activation, and drug response to targeted therapies.
Main Results:
- 5' fusion partners primarily enhance canonical BRAF oncogenic activity by replacing its auto-inhibitory N-terminal region.
- The specific 5' partner affects BRAF fusions' subcellular localization, signaling capacity, and gene expression profiles.
- All investigated BRAF fusions conferred resistance to EGFR-targeted monotherapy and showed varying sensitivities to combinatorial MEK and EGFR inhibition.
Conclusions:
- BRAF fusion partners significantly influence intracellular signaling and targeted therapy sensitivity.
- All BRAF fusions investigated demonstrated resistance to EGFR-targeted therapy, irrespective of the fusion partner.
- Screening for BRAF fusions alongside other MAPK pathway alterations is crucial for identifying colorectal cancer patients unlikely to benefit from anti-EGFR therapy.
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