Rho-mediated signaling promotes BRAF inhibitor resistance in de-differentiated melanoma cells

Over half of cutaneous melanoma tumors have BRAF V600E/K mutations. Acquired resistance to BRAF inhibitors (BRAFi) remains a major hurdle in attaining durable therapeutic responses. In this study we demonstrate that ~50–60% of melanoma cell lines with vemurafenib resistance acquired in vitro show ac...

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Bibliographic Details
Published in:	Oncogene Vol. 39; no. 7; pp. 1466 - 1483
Main Authors:	Misek, S. A., Appleton, K. M., Dexheimer, T. S., Lisabeth, E. M., Lo, R. S., Larsen, S. D., Gallo, K. A., Neubig, R. R.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 13-02-2020 Nature Publishing Group
Subjects:	13/106 13/95 14/63 38 38/39 38/77 38/90 38/91 631/67/1059/2326 631/67/1813/1634 82/29 Adaptor Proteins, Signal Transducing - metabolism Apoptosis Cancer Care and treatment Cell activation Cell Biology Cell Dedifferentiation - drug effects Cell differentiation Cell Line, Tumor Cell lines Drug resistance Enzyme Activation - drug effects G proteins Gene expression Genes Genetic transcription Health aspects Human Genetics Humans Internal Medicine Kinases Learning algorithms Machine learning Medicine Medicine & Public Health Melanocytes - drug effects Melanocytes - pathology Melanoma Melanoma - pathology Oncology Protein Kinase Inhibitors - pharmacology Proto-Oncogene Proteins B-raf - antagonists & inhibitors Rho-associated kinase rho-Associated Kinases - metabolism RhoA protein Signal Transduction - drug effects Transcription Transcription Factors - metabolism Transcription, Genetic - drug effects Tumors Vemurafenib YAP-Signaling Proteins Yes-associated protein
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Summary:	Over half of cutaneous melanoma tumors have BRAF V600E/K mutations. Acquired resistance to BRAF inhibitors (BRAFi) remains a major hurdle in attaining durable therapeutic responses. In this study we demonstrate that ~50–60% of melanoma cell lines with vemurafenib resistance acquired in vitro show activation of RhoA family GTPases. In BRAFi-resistant melanoma cell lines and tumors, activation of RhoA is correlated with decreased expression of melanocyte lineage genes. Using a machine learning approach, we built gene expression-based models to predict drug sensitivity for 265 common anticancer compounds. We then projected these signatures onto the collection of TCGA cutaneous melanoma and found that poorly differentiated tumors were predicted to have increased sensitivity to multiple Rho kinase (ROCK) inhibitors. Two transcriptional effectors downstream of Rho, MRTF and YAP1, are activated in the Rho High BRAFi-resistant cell lines, and resistant cells are more sensitive to inhibition of these transcriptional mechanisms. Taken together, these results support the concept of targeting Rho-regulated gene transcription pathways as a promising therapeutic approach to restore sensitivity to BRAFi-resistant tumors or as a combination therapy to prevent the onset of drug resistance.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0950-9232 1476-5594 1476-5594
DOI:	10.1038/s41388-019-1074-1