ArticleClinical cancer research : an official journal of the American Association for Cancer Research2013
Resistance to BRAF inhibition in BRAF-mutant colon cancer can be overcome with PI3K inhibition or demethylating agents.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 170 papers, 1 of them a synthesis that pooled it.
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Who cites it
170 citing papers in PubMed, 1 synthesis or guideline pooled it, 297 citations in OpenAlex.
- Systematic review of combinations of targeted or immunotherapy in advanced solid tumors.Journal for immunotherapy of cancer · 2021Pooled it
- Combined BRAF and MEK Inhibition With Dabrafenib and Trametinib in BRAF V600-Mutant Colorectal Cancer.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2015Trial
- Phase II Pilot Study of Vemurafenib in Patients With Metastatic BRAF-Mutated Colorectal Cancer.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2015Trial
- Bcl-2 stabilization by paxillin confers 5-fluorouracil resistance in colorectal cancer.Cell death and differentiation · 2015Trial
- Understanding the Promise and Challenges of Tumor-Agnostic Therapy: Could One Size Really Fit All?Cancers · 2026Review
- RAS signaling in lung adenocarcinoma is defined by lineage context and DUSP4 loss.JCI insight · 2026Article
- The construction of a prognostic nomogram model for colorectal cancer and the prediction of immune characteristics and immune treatment responses based on the bioinformatics analysis of soluble mediator-related genes.Human vaccines & immunotherapeutics · 2025Article
- DNA, RNA, and histone methylation regulation enzymes and their crosstalk in colorectal carcinogenesis and progression: a review of molecular mechanisms, clinical implications, and future perspectives.Cellular & molecular biology letters · 2025Review
- Progress in Drug-targeted Therapy for Papillary Thyroid Carcinoma.Current oncology reports · 2025Review
- scGSDR: Harnessing gene semantics for single-cell pharmacological profiling.Communications biology · 2025Article
- Co-targeting SRC overcomes resistance to BRAF inhibitors in colorectal cancer.British journal of cancer · 2025Article
- The present and future of precision oncology and tumor-agnostic therapeutic approaches.The oncologist · 2025Review
- Article
- HDAC and MEK inhibition synergistically suppresses HOXC6 and enhances PD-1 blockade efficacy in BRAFJournal for immunotherapy of cancer · 2025Article
- Epigenome Reprogramming Through H3K27 and H3K4 Trimethylation as a Resistance Mechanism to DNA Methylation Inhibition in BRAFV600E-Mutated Colorectal Cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2024Article
- Novel Oncogenic Value of C10orf90 in Colon Cancer Identified as a Clinical Diagnostic and Prognostic Marker.International journal of molecular sciences · 2024Article
- Enhanced anti-tumor effects by combination of tucatinib and radiation in HER2-overexpressing human cancer cell lines.Cancer cell international · 2024Article
- The role of PIK3CA gene mutations in colorectal cancer and the selection of treatment strategies.Frontiers in pharmacology · 2024Review
- HSPA8 Activates Wnt/β-Catenin Signaling to Facilitate BRAF V600E Colorectal Cancer Progression by CMA-Mediated CAV1 Degradation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Review
110 more citing papers are in PubMed but not listed here.
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Authors and funding
18 authors at 5 institutions in 2 countries.
Funding
Abstract
purposeVemurafenib, a selective inhibitor of BRAF(V600), has shown significant activity in BRAF(V600) melanoma but not in less than 10% of metastatic BRAF(V600) colorectal cancers (CRC), suggesting that studies of the unique hypermethylated phenotype and concurrent oncogenic activation of BRAF(mut) CRC may provide combinatorial strategies. EXPERIMENTAL
designWe conducted comparative proteomic analysis of BRAF(V600E) melanoma and CRC cell lines, followed by correlation of phosphoinositide 3-kinase (PI3K) pathway activation and sensitivity to the vemurafenib analogue PLX4720. Pharmacologic inhibitors and siRNA were used in combination with PLX4720 to inhibit PI3K and methyltransferase in cell lines and murine models.
resultsCompared with melanoma, CRC lines show higher levels of PI3K/AKT pathway activation. CRC cell lines with mutations in PTEN or PIK3CA were less sensitive to growth inhibition by PLX4720 (P = 0.03), and knockdown of PTEN expression in sensitive CRC cells reduced growth inhibition by the drug. Combined treatment of PLX4720 with PI3K inhibitors caused synergistic growth inhibition in BRAF-mutant CRC cells with both primary and secondary resistance. In addition, methyltransferase inhibition was synergistic with PLX4720 and decreased AKT activation. In vivo, PLX4720 combined with either inhibitors of AKT or methyltransferase showed greater tumor growth inhibition than PLX4720 alone. Clones with acquired resistance to PLX4720 in vitro showed PI3K/AKT activation with EGF receptor (EGFR) or KRAS amplification.
conclusionsWe show that activation of the PI3K/AKT pathway is a mechanism of both innate and acquired resistance to BRAF inhibitors in BRAF(V600E) CRC and suggest combinatorial approaches to improve outcomes in this poor prognosis subset of patients.
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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.