The mechanisms behind UVB-initiated, neonatal-specific melanoma linked to BRAF are not well understood, particularly regarding its role in growth arrest. We found that, beyond mutations, neonatal UV irradiation or Lkb1 loss promotes a cell-autonomous transcriptional reprogramming that prevents BRAF-induced growth arrest, leading to melanoma development. Using UVB-dependent and independent mouse models, genomic analyses, clinical data, and single-cell transcriptomics, we identified a transcriptional program that bypasses growth arrest, promoting melanoma. In humans, many of these genes are linked to poor survival and are upregulated in melanoma progression and other RAS pathway-driven tumors. Reconstitution experiments showed these genes cooperate with BRAF in melanocyte transformation, dedifferentiation, and drug resistance. Depleting gene products like UPP1 highlights their potential as therapeutic targets. Our findings reveal that BRAF-mutated melanomas can develop independently of nevus progression and identify novel targets for treatment.
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