ArticleOncotarget2016
Effects of RAF inhibitors on PI3K/AKT signalling depend on mutational status of the RAS/RAF signalling axis.
Article in Oncotarget, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 19 citations in OpenAlex.
- KBTBD8/RRP15 as a potential novel therapeutic target associates with lenvatinib-inhibited progression in hepatocellular carcinoma both in vitro and in vivo.Journal of advanced research · 2025Article
- Crosstalk between protein kinases AKT and ERK1/2 in human lung tumor-derived cell models.Frontiers in oncology · 2022Article
- Computational quantification of global effects induced by mutations and drugs in signaling networks of colorectal cancer cells.Scientific reports · 2021Article
- Targeting ERK-Hippo Interplay in Cancer Therapy.International journal of molecular sciences · 2020Review
- Anti-angiogenic effects of the blue-green alga Arthrospira platensis on pancreatic cancer.Journal of cellular and molecular medicine · 2020Article
- Article
- Perspectives of RAS and RHEB GTPase Signaling Pathways in Regenerating Brain Neurons.International journal of molecular sciences · 2018Review
- Alterations of mTOR signaling impact metabolic stress resistance in colorectal carcinomas with BRAF and KRAS mutations.Scientific reports · 2018Article
- Pan-RAF and MEK vertical inhibition enhances therapeutic response in non-V600 BRAF mutant cells.BMC cancer · 2018Article
- KRAS mutant allele-specific expression knockdown in pancreatic cancer model with systemically delivered bi-shRNA KRAS lipoplex.PloS one · 2018Article
- An engineered protein antagonist of K-Ras/B-Raf interaction.Scientific reports · 2017Article
- Oncogenic β-catenin and PIK3CA instruct network states and cancer phenotypes in intestinal organoids.The Journal of cell biology · 2017Article
- An immediate-late gene expression module decodes ERK signal duration.Molecular systems biology · 2017Article
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Targeted therapies within the RAS/RAF/MEK/ERK signalling axis become increasingly popular, yet cross-talk and feedbacks in the signalling network lead to unexpected effects. Here we look systematically into how inhibiting RAF and MEK with clinically relevant inhibitors result in changes in PI3K/AKT activation. We measure the signalling response using a bead-based ELISA, and use a panel of three cell lines, and isogenic cell lines that express mutant forms of the oncogenes KRAS and BRAF to interrogate the effects of the MEK and RAF inhibitors on signalling. We find that treatment with the RAF inhibitors have opposing effects on AKT phosphorylation depending on the mutational status of two important oncogenes, KRAS and BRAF. If these two genes are in wildtype configuration, RAF inhibitors reduce AKT phosphorylation. In contrast, if BRAF or KRAS are mutant, RAF inhibitors will leave AKT phosphorylation unaffected or lead to an increase of AKT phosphorylation. Down-regulation of phospho-AKT by RAF inhibitors also extends to downstream transcription factors, and correlates with apoptosis induction. Our results show that oncogenes rewire signalling such that targeted therapies can have opposing effects on parallel pathways, which depend on the mutational status of the cell.
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