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SRC-RAC1 signaling drives drug resistance to BRAF inhibition in de-differentiated cutaneous melanomas

Rare gain-of-function mutations in RAC1 drive drug resistance to targeted BRAF inhibition in cutaneous melanoma. Here, we show that wildtype RAC1 is a critical driver of growth and drug resistance, but only in a subset of melanomas with elevated markers of de-differentiation. Similarly, SRC inhibiti...

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Bibliographic Details
Published in:NPJ precision oncology 2022-10, Vol.6 (1), p.74-74, Article 74
Main Authors: Zhu, Eliot Y., Riordan, Jesse D., Vanneste, Marion, Henry, Michael D., Stipp, Christopher S., Dupuy, Adam J.
Format: Article
Language:English
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Summary:Rare gain-of-function mutations in RAC1 drive drug resistance to targeted BRAF inhibition in cutaneous melanoma. Here, we show that wildtype RAC1 is a critical driver of growth and drug resistance, but only in a subset of melanomas with elevated markers of de-differentiation. Similarly, SRC inhibition also selectively sensitized de-differentiated melanomas to BRAF inhibition. One possible mechanism may be the suppression of the de-differentiated state, as SRC and RAC1 maintained markers of de-differentiation in human melanoma cells. The functional differences between melanoma subtypes suggest that the clinical management of cutaneous melanoma can be enhanced by the knowledge of differentiation status. To simplify the task of classification, we developed a binary classification strategy based on a small set of ten genes. Using this gene set, we reliably determined the differentiation status previously defined by hundreds of genes. Overall, our study informs strategies that enhance the precision of BRAFi by discovering unique vulnerabilities of the de-differentiated cutaneous melanoma subtype and creating a practical method to resolve differentiation status.
ISSN:2397-768X
2397-768X
DOI:10.1038/s41698-022-00310-7