ArticleCancer research2025
Tumorigenesis Driven by BRAFV600E Requires Secondary Mutations That Overcome Its Feedback Inhibition of RAC1 and Migration.
Article in Cancer research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Integrated clinicogenomic analysis reveals the evolution and metastatic tropisms of advanced colorectal cancer.Cancer cell · 2026Article
- Rapid activation of ARF6 after RAF inhibition augments BRAFOncogene · 2026Article
- Rho GTPases in cancer resistance: mechanisms, vulnerabilities, and therapeutic opportunities.Biochemical Society transactions · 2026Review
- Cholecystokinin A Receptor Knockdown Diminishes Colon Cancer Cell Invasive Potential via Modulation of Integrin/FAK, EMT, and uPA/uPAR/MMP2 Axis.Oncology research · 2026Article
- New insights into the classification of the RAC1 P29S hotspot mutation in melanoma as an oncogene.Cancer gene therapy · 2025Article
- A critical role of FAK signaling in Rac1-driven melanoma cell resistance to MAPK pathway inhibition.Oncogene · 2025Article
- Rapid activation of ARF6 after RAF inhibition augments BRAFV600E and promotes therapy resistance.Research square · 2025Article
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19 authors.
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Abstract
BRAF V600E mutations occur in 46% of melanomas and drive high levels of ERK activity and ERK-dependent proliferation. However, BRAFV600E is insufficient to drive melanoma in genetically engineered mouse models, and 82% of human benign nevi harbor BRAFV600E mutations. We found that BRAFV600E inhibited mesenchymal migration by causing feedback inhibition of RAC1 activity. ERK pathway inhibition induced RAC1 activation and restored migration and invasion. In cells with BRAFV600E, mutant RAC1 or PTEN inactivation restored RAC1 activity and cell motility. Together, these lesions occurred in 26% of melanomas with BRAFV600E mutations. Thus, although BRAFV600E activation of ERK deregulates cell proliferation, it prevents full malignant transformation by causing feedback inhibition of RAC1. Secondary mutations are, therefore, required for tumorigenesis. One mechanism underlying tumor evolution may be the selection of lesions that rescue the deleterious effects of oncogenic drivers. Significance: Secondary genetic lesions that rescue BRAFV600E/ERK-induced feedback inhibition on cell migration are required for tumorigenesis, indicating that oncogenic feedback may shape the genetic landscape and select for mutations that are therapeutic targets.
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