Reference Detail

Ref Type

Journal Article

PMID

(36856908)

Authors

Nakai C, Mimaki S, Matsushima K, Shinozaki E, Yamazaki K, Muro K, Yamaguchi K, Nishina T, Yuki S, Shitara K, Bando H, Suzuki Y, Akagi K, Nomura S, Fujii S, Sugiyama M, Nishida N, Mizokami M, Koh Y, Koshizaka T, Okada H, Abe Y, Ohtsu A, Yoshino T, Tsuchihara K

Title

Regulation of MEK inhibitor selumetinib sensitivity by AKT phosphorylation in the novel BRAF L525R mutant.

Journal	Vol	Issue	Date	Pages	Journal Short Title
International journal of clinical oncology			2023 Mar 01	654-663	Int J Clin Oncol

URL

Abstract Text

Oncogenic mutations in BRAF genes are found in approximately 5-10% of colorectal cancers. The majority of BRAF mutations are located within exons 11-15 of the catalytic kinase domains, with BRAF V600E accounting for more than 80% of the observed BRAF mutations. Sensitivity to BRAF- and mitogen-activated protein kinase (MEK) inhibitors varies depending on BRAF mutations and tumor cell types. Previously, we newly identified, BRAF L525R-mutation, in the activation segment of the kinase in colorectal cancer patient. Here, we characterized the function of the BRAF L525R mutation.HEK293 cells harboring a BRAF mutation (V600E or L525R) were first characterized and then treated with cetuximab, dabrafenib, and selumetinib. Cell viability was measured using WST-1 assay and the expression of proteins involved in the extracellular signal-regulated kinase (ERK) and protein kinase B (AKT) signaling pathways was evaluated using western blot analysis.The MEK inhibitor selumetinib effectively inhibited cell proliferation and ERK phosphorylation in BRAF L525R cells but not in BRAF V600E cells. Further studies revealed that AKT phosphorylation was reduced by selumetinib in BRAF L525R cells but not in BRAF V600E cells or selumetinib-resistant BRAF L525R cells. Moreover, the AKT inhibitor overcame the selumetinib resistance.We established a model system harboring BRAF L525R using HEK293 cells. BRAF L525R constitutively activated ERK. AKT phosphorylation caused sensitivity and resistance to selumetinib. Our results suggest that a comprehensive network analysis may provide insights to identify effective therapies.

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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 L525R	Advanced Solid Tumor	sensitive	Selumetinib	Preclinical - Cell culture	Actionable	In a preclinical study, Koselugo (selumetinib) inhibited viability of cells expressing BRAF L525R in culture (PMID: 36856908).	36856908
BRAF L525R	Advanced Solid Tumor	sensitive	Dactolisib	Preclinical - Cell culture	Actionable	In a preclinical study, Dactolisib (BEZ235) inhibited viability of cells expressing BRAF L525R in culture (PMID: 36856908).	36856908
BRAF L525R	Advanced Solid Tumor	predicted - sensitive	Dactolisib + Selumetinib	Preclinical - Cell culture	Actionable	In a preclinical study, the addition of Dactolisib (BEZ235) to treatment with Koselugo (selumetinib) resulted in increased inhibition of proliferation in Koselugo (selumetinib)-resistant cells expressing BRAF L525R compared to Dactolisib (BEZ235) alone (PMID: 36856908).	36856908