ArticleMolecular cancer therapeutics2015
Combined Pan-RAF and MEK Inhibition Overcomes Multiple Resistance Mechanisms to Selective RAF Inhibitors.
Article in Molecular cancer therapeutics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers, 2 of them syntheses that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
52 citing papers in PubMed, 2 syntheses or guidelines pooled it, 71 citations in OpenAlex.
- Signaling pathway mechanisms in pancreatic ductal adenocarcinoma tumor microenvironment and emerging targeting strategies for improved prognosis.Oncology reviews · 2026Pooled it
- A comprehensive overview of the molecular features and therapeutic targets in BRAFClinical and translational medicine · 2024Pooled it
- Efficacy and safety of regorafenib in patients with advanced pretreated melanoma: results of the RegoMel phase II clinical trial.ESMO open · 2026Trial
- Review
- Combination of the Novel RAF Dimer Inhibitor Brimarafenib With the MEK Inhibitor Mirdametinib Is Effective Against NRAS Mutant Melanoma.Pigment cell & melanoma research · 2025Article
- Selective inhibition of BRAF and CRAF sensitizes NF1-deficient malignant peripheral nerve sheath tumors to MEK inhibitors.Molecular medicine (Cambridge, Mass.) · 2025Article
- Preclinical Activity of the Type II RAF Inhibitor Tovorafenib in Tumor Models Harboring Either a BRAF Fusion or an NF1 Loss-of-Function Mutation.Cancer research communications · 2025Article
- Regorafenib Combined with BRAF/MEK Inhibitors for the Treatment of Refractory Melanoma Brain Metastases.Cancers · 2024Article
- Expanding the landscape of oncogenic drivers and treatment options in acral and mucosal melanomas by targeted genomic profiling.International journal of cancer · 2024Article
- Current State of Targeted Therapy in Adult Langerhans Cell Histiocytosis and Erdheim-Chester Disease.Targeted oncology · 2024Review
- Article
- Computational modeling of drug response identifies mutant-specific constraints for dosing panRAF and MEK inhibitors in melanoma.bioRxiv : the preprint server for biology · 2024Article
- ERK pathway agonism for cancer therapy: evidence, insights, and a target discovery framework.NPJ precision oncology · 2024Review
- Cosmosiin Induces Apoptosis in Colorectal Cancer by Inhibiting PD-L1 Expression and Inducing ROS.Antioxidants (Basel, Switzerland) · 2023Article
- Targeting the RAS/RAF/MAPK pathway for cancer therapy: from mechanism to clinical studies.Signal transduction and targeted therapy · 2023Review
- Computational biophysics approach towards the discovery of multi-kinase blockers for the management of MAPK pathway dysregulation.Molecular diversity · 2023Article
- Rational combinations of targeted cancer therapies: background, advances and challenges.Nature reviews. Drug discovery · 2023Review
- Integrated Decision-Making in the Treatment of Colon-Rectal Cancer: The Case of KRAS-Mutated Tumors.Life (Basel, Switzerland) · 2023Review
- Optimizing the first-line treatment for metastatic colorectal cancer.Frontiers in oncology · 2023Review
- Resistance mechanisms in BRAFFrontiers in oncology · 2022Review
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
RAF and MEK inhibitors are effective in BRAF-mutant melanoma but not in BRAF-mutant colorectal cancer. To gain additional insights into this difference, we performed a genome-scale pooled shRNA enhancer screen in a BRAF-mutant, RAF inhibitor-resistant colorectal cancer cell line exposed to the selective RAF inhibitor PLX4720. We identified multiple genes along the receptor tyrosine kinase (RTK)/mitogen-activated protein kinase (MAPK) signaling axis that, when suppressed, either genetically or pharmacologically, sensitized cells to the selective RAF inhibitor through sustained inhibition of MAPK signaling. Strikingly, CRAF was a key mediator of resistance that could be overcome by the use of pan-RAF inhibitors in combination with a MEK inhibitor. Furthermore, the combination of pan-RAF and MEK inhibitors displayed strong synergy in melanoma and colorectal cancer cell lines with RAS-activating events such as RTK activation, KRAS mutation, or NF1 loss-of-function mutations. Combinations of selective RAF inhibitors, such as PLX4720 or dabrafenib, with MEK inhibitors did not incur such profound synergy, suggesting that inhibition of CRAF by pan-RAF inhibitors plays a key role in determining cellular response. Importantly, in contrast to the modest activity seen with single-agent treatment, dual pan-RAF and MEK inhibition results in the induction of apoptosis, greatly enhancing efficacy. Notably, combined pan-RAF and MEK inhibition can overcome intrinsic and acquired resistance to single-agent RAF/MEK inhibition, supporting dual pan-RAF and MEK inhibition as a novel therapeutic strategy for BRAF- and KRAS-mutant cancers.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.