ArticleClinical cancer research : an official journal of the American Association for Cancer Research2020
Targeting Extracellular Matrix Remodeling Restores BRAF Inhibitor Sensitivity in BRAFi-resistant Melanoma.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 44 citations in OpenAlex.
- MAPK Inhibitor-Tolerant Persister Cells in Melanoma: Mechanisms and Therapeutic Vulnerabilities.Cancer science · 2026Review
- Targeting the microbiota-miRNA-protease axis: A new therapeutic avenue in melanoma.The FEBS journal · 2026Review
- Extracellular matrix stiffness determines the phenotypic behavior of dedifferentiated melanoma cells through a DDR1/2-dependent YAP mechanotransduction pathway.Oncogenesis · 2026Article
- TGF-β in tumor development and progression: mechanisms and therapeutics.Molecular biomedicine · 2026Review
- Matrix Metalloproteinase Inhibition in Melanoma.Experimental dermatology · 2026Review
- Development of Tumor Microenvironment-Responsive Nanoparticles with Enhanced Tissue Penetration.Nanomaterials (Basel, Switzerland) · 2025Article
- Therapy-Induced ECM Remodeling Creates a Transient Immune Barrier in Residual Melanoma.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Phenotype switching in highly invasive resistant to vemurafenib and cobimetinib melanoma cells.Cell communication and signaling : CCS · 2025Article
- Co-inhibition of Notch1 and ChK1 triggers genomic instability and melanoma cell death increasing the lifespan of mice bearing melanoma brain metastasis.Journal of experimental & clinical cancer research : CR · 2025Article
- Interfering Nuclear Protein Laminb1 Induces DNA Damage and Reduces Vemurafenib Resistance in Melanoma Cells In Vitro.Cancers · 2024Article
- Notch1 blockade by a novel, selective anti-Notch1 neutralizing antibody improves immunotherapy efficacy in melanoma by promoting an inflamed TME.Journal of experimental & clinical cancer research : CR · 2024Article
- Proteogenomic characterization of skull-base chordoma.Nature communications · 2024Article
- Skin Malignant Melanoma and Matrix Metalloproteinases: Promising Links to Efficient Therapies.International journal of molecular sciences · 2024Review
- Clonal differences underlie variable responses to sequential and prolonged treatment.Cell systems · 2024Article
- USP51/PD-L1/ITGB1-deployed juxtacrine interaction plays a cell-intrinsic role in promoting chemoresistant phenotypes in non-small cell lung cancer.Cancer communications (London, England) · 2023Article
- BRAF V600-Mutated Metastatic Melanoma and Targeted Therapy Resistance: An Update of the Current Knowledge.Cancers · 2023Review
- The mechanical phenotypic plasticity of melanoma cell: an emerging driver of therapy cross-resistance.Oncogenesis · 2023Review
- New Insights into the Phenotype Switching of Melanoma.Cancers · 2022Review
- Single-cell RNA sequencing depicts the local cell landscape in thyroid-associated ophthalmopathy.Cell reports. Medicine · 2022Article
- Vemurafenib Drives Epithelial-to-Mesenchymal Transition Gene Expression in BRAF Inhibitor‒Resistant BRAFThe Journal of investigative dermatology · 2022Article
Corrections and comments
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Authors and funding
21 authors at 7 institutions in 1 country.
Funding
Abstract
purposeThe extracellular matrix (ECM) is an intriguing, yet understudied component of therapy resistance. Here, we investigated the role of ECM remodeling by the collagenase, MT1-MMP, in conferring resistance of v-Raf murine sarcoma viral oncogene homolog B1 (BRAF)-mutant melanoma to BRAF inhibitor (BRAFi) therapy. EXPERIMENTAL
designPublicly available RNA-sequencing data and reverse phase protein array were used to determine the relevance of MT1-MMP upregulation in BRAFi-resistant melanoma in patients, patient-derived xenografts, and cell line-derived tumors. Short hairpin RNA (shRNA)-mediated knockdown of MT1-MMP, inhibition via the selective MT1-MMP/MMP2 inhibitor, ND322, or overexpression of MT1-MMP was used to assess the role of MT1-MMP in mediating resistance to BRAFi.
resultsMT1-MMP was consistently upregulated in posttreatment tumor samples derived from patients upon disease progression and in melanoma xenografts and cell lines that acquired resistance to BRAFi. shRNA- or ND322-mediated inhibition of MT1-MMP synergized with BRAFi leading to resensitization of resistant cells and tumors to BRAFi. The resistant phenotype depends on the ability of cells to cleave the ECM. Resistant cells seeded in MT1-MMP uncleavable matrixes were resensitized to BRAFi similarly to MT1-MMP inhibition. This is due to the inability of cells to activate integrinβ1 (ITGB1)/FAK signaling, as restoration of ITGB1 activity is sufficient to maintain resistance to BRAFi in the context of MT1-MMP inhibition. Finally, the increase in MT1-MMP in BRAFi-resistant cells is TGFβ dependent, as inhibition of TGFβ receptors I/II dampens MT1-MMP overexpression and restores sensitivity to BRAF inhibition.
conclusionsBRAF inhibition results in a selective pressure toward higher expression of MT1-MMP. MT1-MMP is pivotal to an ECM-based signaling pathway that confers resistance to BRAFi therapy.
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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.