ArticleMolecular pharmacology2022
Ibrutinib Blocks YAP1 Activation and Reverses BRAF Inhibitor Resistance in Melanoma Cells.
Article in Molecular pharmacology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 15 citations in OpenAlex.
- Decoding the Histomorphological and Multi-Omic Characteristics of Melanotic Schwannoma.Current medical science · 2026Article
- Article
- Functional proteoform group deconvolution reveals a broader spectrum of ibrutinib off-targets.Nature communications · 2025Article
- RNF144A-AS1 stabilizes TAF15 and promotes malignant biological behaviors of skin cutaneous melanoma.Molecular and cellular biochemistry · 2025Article
- TransCell: In Silico Characterization of Genomic Landscape and Cellular Responses by Deep Transfer Learning.Genomics, proteomics & bioinformatics · 2024Article
- Ibrutinib Modulates Proliferation, Migration, Mitochondrial Homeostasis, and Apoptosis in Melanoma Cells.Biomedicines · 2024Article
- Computational discovery of co-expressed antigens as dual targeting candidates for cancer therapy through bulk, single-cell, and spatial transcriptomics.Bioinformatics advances · 2024Article
- Epstein-Barr virus LMP1 protein promotes proliferation and inhibits differentiation of epithelial cells via activation of YAP and TAZ.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Hierarchical multi-omics data integration and modeling predict cell-specific chemical proteomics and drug responses.Cell reports methods · 2023Article
- Reversal of cancer gene expression identifies repurposed drugs for diffuse intrinsic pontine glioma.Acta neuropathologica communications · 2022Article
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
Most B-Raf proto-oncogene (BRAF)-mutant melanoma tumors respond initially to BRAF inhibitor (BRAFi)/mitogen-activated protein kinase kinase 1 inhibitor (MEKi) therapy, although few patients have durable long-term responses to these agents. The goal of this study was to use an unbiased computational approach to identify inhibitors that reverse an experimentally derived BRAFi resistance gene expression signature. Using this approach, we found that ibrutinib effectively reverses this signature, and we demonstrate experimentally that ibrutinib resensitizes a subset of BRAFi-resistant melanoma cells to vemurafenib. Ibrutinib is used clinically as an inhibitor of the Src family kinase Bruton tyrosine kinase (BTK); however, neither BTK deletion nor treatment with acalabrutinib, another BTK inhibitor with reduced off-target activity, resensitized cells to vemurafenib. These data suggest that ibrutinib acts through a BTK-independent mechanism in vemurafenib resensitization. To better understand this mechanism, we analyzed the transcriptional profile of ibrutinib-treated BRAFi-resistant melanoma cells and found that the transcriptional profile of ibrutinib was highly similar to that of multiple Src proto-oncogene kinase inhibitors. Since ibrutinib, but not acalabrutinib, has appreciable off-target activity against multiple Src family kinases, it suggests that ibrutinib may be acting through this mechanism. Furthermore, genes that are differentially expressed in ibrutinib-treated cells are enriched in Yes1-associated transcriptional regulator (YAP1) target genes, and we showed that ibrutinib, but not acalabrutinib, reduces YAP1 activity in BRAFi-resistant melanoma cells. Taken together, these data suggest that ibrutinib, or other Src family kinase inhibitors, may be useful for treating some BRAFi/MEKi-refractory melanoma tumors. SIGNIFICANCE STATEMENT: MAPK-targeted therapies provide dramatic initial responses, but resistance develops rapidly; a subset of these tumors may be rendered sensitive again by treatment with an approved Src family kinase inhibitor-ibrutinub-potentially providing improved clinical outcomes.
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