Reference Detail

Ref Type

Journal Article

PMID

(31704811)

Authors

Lehtomaki KI, Lahtinen LI, Rintanen N, Kuopio T, Kholova I, Makela R, Rantala JK, Kellokumpu-Lehtinen PL, Kononen J

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Anticancer research	39	11	2019 Nov	5867-5877	Anticancer Res

URL

Abstract Text

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.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.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.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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF L597Q	colon adenocarcinoma	predicted - sensitive	Selumetinib	Preclinical - Patient cell culture	Actionable	In a preclinical study, Koselugo (selumetinib) inhibited growth of tumor cells derived from the metachronous para-aortal lymph node metastasis harboring BRAF L597Q, which was resected from a patient with colon adenocarcinoma (PMID: 31704811).	31704811
BRAF L597Q	colon adenocarcinoma	predicted - sensitive	Cetuximab + Trametinib	Preclinical - Patient cell culture	Actionable	In a preclinical study, Mekinist (trametinib) and Erbitux (cetuximab) synergistically inhibited growth of tumor cells derived from the metachronous para-aortal lymph node metastasis harboring BRAF L597Q, which was resected from a patient with colon adenocarcinoma (PMID: 31704811).	31704811
BRAF L597Q	colon adenocarcinoma	predicted - sensitive	Sapitinib	Preclinical - Patient cell culture	Actionable	In a preclinical study, Sapitinib (AZD8931) inhibited growth of tumor cells derived from the metachronous para-aortal lymph node metastasis harboring BRAF L597Q, which was resected from a patient with colon adenocarcinoma (PMID: 31704811).	31704811
BRAF L597Q	colon adenocarcinoma	predicted - sensitive	Trametinib	Preclinical - Patient cell culture	Actionable	In a preclinical study, Mekinist (trametinib) inhibited growth of tumor cells derived from the metachronous para-aortal lymph node metastasis harboring BRAF L597Q, which was resected from a patient with colon adenocarcinoma (PMID: 31704811).	31704811