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

• 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: England Nature Publishing Group 01.02.2020
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Cancer; Care and treatment; Cell activation; 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; Humans; Kinases; Learning algorithms; Machine learning; Melanocytes - drug effects; Melanocytes - pathology; Melanoma; Melanoma - pathology; 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
• ISSN: 0950-9232; 1476-5594; 1476-5594
• DOI: 10.1038/s41388-019-1074-1

Over half of cutaneous melanoma tumors have BRAF 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 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.