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

Oncogene volume 39, pages 1466–1483 (2020)Cite this article

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Abstract

Over half of cutaneous melanoma tumors have BRAFV600E/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 RhoHigh 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.

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Acknowledgements

This work was supported by NIH R01 AR066049 (SDL), the MSU Gran Fondo Skin Cancer Research Fund (RRN), NIH F31 CA232555 (SAM), MSUFCU Aitch Foundation Fellowship (SAM).

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Authors and Affiliations

  1. Department of Physiology, Michigan State University, East Lansing, MI, 48824, USA

    S. A. Misek & K. A. Gallo

  2. Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, 48824, USA

    K. M. Appleton, T. S. Dexheimer, E. M. Lisabeth & R. R. Neubig

  3. Division of Dermatology, Department of Medicine, University of California, Los Angeles, CA, 90095, USA

    R. S. Lo

  4. Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, 90095, USA

    R. S. Lo

  5. Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, 90095, USA

    R. S. Lo

  6. David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA

    R. S. Lo

  7. Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI, 48109, USA

    S. D. Larsen

  8. Vahlteich Medicinal Chemistry Core, University of Michigan, Ann Arbor, MI, 48109, USA

    S. D. Larsen

  9. Nicholas V. Perricone, M.D., Division of Dermatology, Department of Medicine, College of Human Medicine, Michigan State University, East Lansing, 48824, MI, USA

    R. R. Neubig

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RRN and SDL have intellectual property rights in the CCG-222740 compound used in this study. They are also founders and officers of FibrosIX Inc. which has an option for the IP for this and related compounds. The remaining authors declare that they have no conflict of interest.

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Misek, S.A., Appleton, K.M., Dexheimer, T.S. et al. Rho-mediated signaling promotes BRAF inhibitor resistance in de-differentiated melanoma cells. Oncogene 39, 1466–1483 (2020). https://doi.org/10.1038/s41388-019-1074-1

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