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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Veröffentlicht in:Oncogene 2020-02, Vol.39 (7), p.1466-1483
Hauptverfasser: Misek, S. A., Appleton, K. M., Dexheimer, T. S., Lisabeth, E. M., Lo, R. S., Larsen, S. D., Gallo, K. A., Neubig, R. R.
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container_end_page 1483
container_issue 7
container_start_page 1466
container_title Oncogene
container_volume 39
creator Misek, S. A.
Appleton, K. M.
Dexheimer, T. S.
Lisabeth, E. M.
Lo, R. S.
Larsen, S. D.
Gallo, K. A.
Neubig, R. R.
description 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.
doi_str_mv 10.1038/s41388-019-1074-1
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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. 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subjects 13/106
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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
title Rho-mediated signaling promotes BRAF inhibitor resistance in de-differentiated melanoma cells
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