SRC-RAC1 signaling drives drug resistance to BRAF inhibition in de-differentiated cutaneous melanomas
Year: 2022
Type: article
Abstract: 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.
Source: npj Precision Oncology
Language: English
Topic: Melanoma and MAPK Pathways
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,390
Funders: U.S. Department of Health and Human Services, American Skin Association, Melanoma Research Foundation, Melanoma Research Alliance, Iowa Department of Public Health, National Institutes of Health, Holden Comprehensive Cancer Center, University of Iowa, National Cancer Institute, National Institute of General Medical Sciences
OpenAlex ID: W4306973406