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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.
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 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
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 sensitive Selumetinib Preclinical - Cell culture Actionable In a preclinical study, Koselugo (selumetinib) inhibited viability of cells expressing BRAF L525R in culture (PMID: 36856908). 36856908