Clonal Evolution of MEK/MAPK Pathway Activating Mutations in a Metastatic Colorectal Cancer Case
Kaisa I Lehtomaki1,2, Laura I Lahtinen3, Nina Rintanen3
1Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland kaisa.lehtomaki@tuni.fi.
Background/Aim:
The aim of this study was to examine clonal heterogeneity, to test the utility of liquid biopsy in monitoring disease progression and to evaluate the usefulness of ex vivo drug screening in a BRAF L597Q-mutated colorectal cancer (CRC) patient developing metastases during adjuvant therapy.
Materials And Methods:
Next generation sequencing (NGS) and droplet digital PCR (ddPCR) were performed in samples from tumor tissues and liquid biopsies. Live cancer cells from a metastatic lesion were used in ex vivo drug sensitivity assays.
Results:
We found evidence of continued dependence of MEK/MAPK pathway activation, but different activating mutations in primary tumor and metastases. Liquid biopsy based BRAF L597Q ddPCR testing was a sensitive personalized biomarker predicting the rise of clinically aggressive metastatic disease. Ex vivo drug sensitivity assays with BRAF L597Q mutated cells showed response to MEK/MAPK targeted therapies.
Conclusion:
The rare BRAF L597Q mutation may be associated with aggressive tumor behavior in CRC. Liquid biopsy can be used to capture clinically relevant tumor features.
Insights
This study shows that liquid biopsy can track aggressive BRAF L597Q-mutated colorectal cancer (CRC) progression. Ex vivo drug screening identified MEK/MAPK targeted therapies as effective treatments.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Investigating clonal heterogeneity in colorectal cancer (CRC).
- Assessing liquid biopsy utility for monitoring disease progression.
- Evaluating ex vivo drug screening in a BRAF L597Q-mutated CRC patient with metastatic disease during adjuvant therapy.
Observation:
- Next-generation sequencing (NGS) and droplet digital PCR (ddPCR) analyzed tumor tissues and liquid biopsies.
- Live cancer cells from metastases underwent ex vivo drug sensitivity assays.
- MEK/MAPK pathway activation persisted, with distinct mutations in primary tumors versus metastases.
Findings:
- Liquid biopsy-based BRAF L597Q ddPCR testing served as a sensitive biomarker for aggressive metastatic CRC.
- Ex vivo drug sensitivity assays demonstrated that BRAF L597Q-mutated cells responded to MEK/MAPK targeted therapies.
Implications:
- The rare BRAF L597Q mutation may indicate aggressive CRC behavior.
- Liquid biopsy effectively captures clinically relevant tumor characteristics.
- Ex vivo drug screening and liquid biopsy offer personalized treatment strategies for CRC.
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