Low-Dose Vertical Inhibition of the RAF-MEK-ERK Cascade Causes Apoptotic Death of KRAS-mutant Cancers
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB38063 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR4080140_1.fastq.gz | Fastqsanger.gz | |||
| ERR4080140_2.fastq.gz | Fastqsanger.gz | |||
| ERR4080150_1.fastq.gz | Fastqsanger.gz | |||
| ERR4080150_2.fastq.gz | Fastqsanger.gz | |||
| ERR4080160_1.fastq.gz | Fastqsanger.gz |
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Project description:We address whether combinations with a pan-RAF inhibitor (RAFi) would be effective in KRAS mutant pancreatic ductal adenocarcinoma (PDAC). Chemical library and CRISPR genetic screens identify combinations causing apoptotic anti-tumor activity. The most potent combination, concurrent inhibition of RAF (RAFi) and ERK (ERKi), is highly synergistic at low doses in cell line, organoid, and rat models of PDAC, whereas each inhibitor alone is only cytostatic. Comprehensive mechanistic signaling studies using reverse phase protein array (RPPA) pathway mapping and RNA sequencing (RNA-seq) show that RAFi/ERKi induced insensitivity to loss of negative feedback and system failures including loss of ERK signaling, FOSL1, and MYC; shutdown of the MYC transcriptome; and induction of mesenchymal-to-epithelial transition. We conclude that low-dose vertical inhibition of the RAF-MEK-ERK cascade is an effective therapeutic strategy for KRAS mutant PDAC.
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Project description:The well-known hepatotoxicity mechanism resulting from alpha-amanitin (-AMA) exposure arises from RNA polymerase II (RNAP II) inhibition. RNAP Ⅱ inhibition occurs through the dysregulation of mRNA synthesis. However, the signaling pathways in hepatocytes that arise from -AMA have not yet been fully elucidated. Here, we identified that the RAS/RAF/ERK signaling pathway was activated through quantitative phosphoproteomic and molecular biological analyses. Bioinformatics analysis showed that AMA exposure increased protein phosphorylation in a time-dependent AMA AMA exposure. In addition, phosphorylation increased not only the components of the ERK signaling pathway but also U2AF65 and SPF45, known splicing factors. Therefore, we propose a novel mechanism of -AMA as follows. The RAS/RAF/ERK signaling pathway involved in aberrant splicing events is activated by -AMA exposure followed by aberrant splicing events leading to cell death.
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Project description:The well-known hepatotoxicity mechanism resulting from alpha-amanitin (-AMA) exposure arises from RNA polymerase II (RNAP II) inhibition. RNAP Ⅱ inhibition occurs through the dysregulation of mRNA synthesis. However, the signaling pathways in hepatocytes that arise from -AMA have not yet been fully elucidated. Here, we identified that the RAS/RAF/ERK signaling pathway was activated through quantitative phosphoproteomic and molecular biological analyses. Bioinformatics analysis showed that AMA exposure increased protein phosphorylation in a time-dependent AMA AMA exposure. In addition, phosphorylation increased not only the components of the ERK signaling pathway but also U2AF65 and SPF45, known splicing factors. Therefore, we propose a novel mechanism of -AMA as follows. The RAS/RAF/ERK signaling pathway involved in aberrant splicing events is activated by -AMA exposure followed by aberrant splicing events leading to cell death.
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Project description:The Raf-MEK-ERK signaling network has been the subject of intense research due to its role in the development of human cancers, including pediatric neuroblastoma (NB). MEK and ERK are the central components of this signaling pathway and are attractive targets for cancer therapy. Approximately 3-5% of the primary NB samples and about 80% of relapsed samples contain mutations in the Raf-MEK-ERK pathway. In the present study, we analyzed the NB patient datasets and revealed that high RAF and MEK expression leads to poor overall survival and directly correlates with cancer progression and relapse. Further, we repurposed a specific small-molecule MEK inhibitor CI-1040 to inhibit the Raf-MEK-ERK pathway in NB. Our results show that CI-1040 potently inhibits NB cell proliferation and clonogenic growth in a dose-dependent manner. Inhibition of the Raf-MEK-ERK pathway by CI-1040 significantly enhances apoptosis, blocks cell cycle progression at the S phase, inhibits expression of the cell cycle-related genes, and significantly inhibits phosphorylation and activation of the ERK1/2 protein. Furthermore, CI-1040 significantly inhibits tumor growth in different NB 3D spheroidal tumor models in a dose-dependent manner and by directly inhibiting spheroidal tumor cells. Overall, our findings highlight that direct inhibition of the Raf-MEK-ERK pathway is a novel therapeutic approach for NB, and further developing repurposing strategies using CI-1040 is a clinically tractable strategy for effectively treating NB.
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Project description:Disruption of the MAPK pathway in cancer by kinase inhibition often fails due to pathway reactivation, causing clinical relapse. Among MAPK inhibitors, type I RAF inhibitors are only active against specific BRAF mutants; MEK inhibitor monotherapy is associated with limited clinical benefits but may serve as a foundation for combinatorial therapy. Here, we show that type II RAF plus allosteric MEK inhibitors durably blunt the development of acquired MEK inhibitor resistance among cancers with KRAS, NRAS, NF1, BRAFnon-V600 and BRAFV600 mutations, when compared to a combination of type II RAF plus ERK inhibitors. Type II RAF and MEK (versus ERK) inhibitors also display superior capacity to sequester MEK in RAF complexes and uncouple MEK and ERK interaction in acquired resistant tumor subpopulations. Systemically and intratumorally, type II RAF plus MEK inhibitors expand memory and activated/exhausted CD8+ T-cells. Whereas trametinib alone temporally reduces dominant intra-tumoral T-cell clones, type II RAF inhibitor co-treatment reverses this effect and promotes T-cell clonotypic expansion and convergence. Importantly, durably control of tumors by this combination requires CD8+ T-cells. Thus, the prolonged anti-tumor efficacy of type II RAF plus MEK inhibitors reveals exquisite MAPK addiction in common lethal cancer histologies, and the mechanisms include unexpected allosteric perturbation of the MAPK pathway and engagement of anti-tumor CD8+ T-cell immunity.
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Project description:Disruption of the MAPK pathway in cancer by kinase inhibition often fails due to pathway reactivation, causing clinical relapse. Among MAPK inhibitors, type I RAF inhibitors are only active against specific BRAF mutants; MEK inhibitor monotherapy is associated with limited clinical benefits but may serve as a foundation for combinatorial therapy. Here, we show that type II RAF plus allosteric MEK inhibitors durably blunt the development of acquired MEK inhibitor resistance among cancers with KRAS, NRAS, NF1, BRAFnon-V600 and BRAFV600 mutations, when compared to a combination of type II RAF plus ERK inhibitors. Type II RAF and MEK (versus ERK) inhibitors also display superior capacity to sequester MEK in RAF complexes and uncouple MEK and ERK interaction in acquired resistant tumor subpopulations. Systemically and intratumorally, type II RAF plus MEK inhibitors expand memory and activated/exhausted CD8+ T-cells. Whereas trametinib alone temporally reduces dominant intra-tumoral T-cell clones, type II RAF inhibitor co-treatment reverses this effect and promotes T-cell clonotypic expansion and convergence. Importantly, durably control of tumors by this combination requires CD8+ T-cells. Thus, the prolonged anti-tumor efficacy of type II RAF plus MEK inhibitors reveals exquisite MAPK addiction in common lethal cancer histologies, and the mechanisms include unexpected allosteric perturbation of the MAPK pathway and engagement of anti-tumor CD8+ T-cell immunity.
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