Clonal Evolution of MEK/MAPK Pathway Activating Mutations in a Metastatic Colorectal Cancer Case.

Abstract

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.

• Authors: Kaisa I Lehtomaki, Laura I Lahtinen, Nina Rintanen, Teijo Kuopio, Ivana Kholova, Rami Makela, Juha K Rantala, Pirkko-Liisa Kellokumpu-Lehtinen, Juha Kononen
• Journal: Anticancer research (Anticancer Res) Vol. 39 Issue 11 Pg. 5867-5877 (Nov 2019) ISSN: 1791-7530 [Electronic] Greece
• PMID: 31704811 (Publication Type: Case Reports, Journal Article)
• Copyright: Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Chemical References

• Biomarkers, Tumor
• Oxaliplatin
• Capecitabine
• Mitogen-Activated Protein Kinases
• MAP Kinase Kinase 1
• MAP2K1 protein, human

Topics

• Aged
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Biomarkers, Tumor (genetics, metabolism)
• Capecitabine (administration & dosage)
• Clonal Evolution
• Colorectal Neoplasms (drug therapy, genetics, pathology)
• Drug Resistance, Neoplasm (genetics)
• Female
• High-Throughput Nucleotide Sequencing
• Humans
• Lung Neoplasms (drug therapy, genetics, secondary)
• MAP Kinase Kinase 1 (genetics, metabolism)
• Mitogen-Activated Protein Kinases (genetics, metabolism)
• Mutation
• Oxaliplatin (administration & dosage)
• Prognosis