SRC-RAC1 signaling drives drug resistance to BRAF inhibition in de-differentiated cutaneous melanomas.
SRC-RAC1 signaling drives drug resistance to BRAF inhibition in de-differentiated cutaneous melanomas.
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DOI：
10.1038/s41698-022-00310-7
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发表时间：
2022-10-21
影响因子：
7.9
通讯作者：
Dupuy, Adam J.
中科院分区：
文献类型：
--
作者：
Zhu, Eliot Y.;Riordan, Jesse D.;Vanneste, Marion;Henry, Michael D.;Stipp, Christopher S.;Dupuy, Adam J.
在皮肤黑色素瘤中，罕见的RAC1功能获得突变驱动靶向BRAF抑制的耐药。在这里，我们表明野生型RAC1是生长和耐药的关键驱动因素，但仅在去分化标记物升高的黑色素瘤亚群中。同样，SRC抑制也选择性地使去分化黑色素瘤对BRAF抑制敏感。一种可能的机制可能是抑制去分化状态，因为SRC和RAC1在人类黑色素瘤细胞中维持去分化标记。黑色素瘤亚型之间的功能差异表明，皮肤黑色素瘤的临床管理可以通过对分化状态的了解来加强。为了简化分类任务，我们开发了一个基于10个基因的小集合的二元分类策略。利用这个基因集，我们可靠地确定了以前由数百个基因定义的分化状态。总的来说，我们的研究通过发现去分化皮肤黑色素瘤亚型的独特脆弱性和创造一种解决分化状态的实用方法，为提高BRAFi的准确性提供了策略。
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.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
64.5
作者：
Hugo W;Shi H;Sun L;Piva M;Song C;Kong X;Moriceau G;Hong A;Dahlman KB;Johnson DB;Sosman JA;Ribas A;Lo RS
通讯作者：
Lo RS
DOI：
10.1111/j.1600-0749.2006.00322.x
发表时间：
2006-08-01
期刊：
PIGMENT CELL RESEARCH
影响因子：
--
作者：
Hoek, Keith S.;Schlegel, Natalie C.;Dummer, Reinhard
通讯作者：
Dummer, Reinhard
DOI：
10.1073/pnas.1216141110
发表时间：
2013-02-19
影响因子：
11.1
作者：
Kawazu, Masahito;Ueno, Toshihide;Mano, Hiroyuki
通讯作者：
Mano, Hiroyuki
影响因子：
64.5
作者：
Hugo W;Zaretsky JM;Sun L;Song C;Moreno BH;Hu-Lieskovan S;Berent-Maoz B;Pang J;Chmielowski B;Cherry G;Seja E;Lomeli S;Kong X;Kelley MC;Sosman JA;Johnson DB;Ribas A;Lo RS
通讯作者：
Lo RS