英国弗朗西斯·克里克研究所Julian Downward小组近日取得一项新成果。他们发现了RAC1P29S通过血清反应因子诱导间充质表型转换，促进黑色素瘤的发生和治疗抵抗。 2019年7月8日出版的《癌细胞》发表了这项成果。

该团队研究了RAC1P29S在黑色素瘤发生发展中的作用，发现RAC1P29S激活PAK、AKT和SRF/MRTF转录通路启动的基因表达程序，导致黑色素细胞向间充质表型转变。小鼠从内基因座泛素化表达RAC1P29S后，发生淋巴瘤。当RAC1P29S仅在黑素细胞中表达时，它与致癌BRAF或 NF1缺失协同作用，促进肿瘤发生。RAC1P29S还驱动对BRAF抑制剂的耐药性，而SRF/MRTF抑制剂逆转了这种耐药性。这些发现证实RAC1P29S是黑色素瘤形成的启动子和治疗抵抗的调节因子，同时确定SRF/MRTF是一个潜在的治疗靶点。

据了解，RAC1 P29是人类皮肤黑色素瘤中排名第三位最常见的突变密码子，仅次于BRAF V600和NRAS Q61。

附：英文原文

Title: RAC1P29S Induces a Mesenchymal Phenotypic Switch via Serum Response Factor to Promote Melanoma Development and Therapy Resistance

Author: Danil A. Lionarons, David C. Hancock, Sareena Rana, Philip East, Christopher Moore, Miguel M. Murillo, Joana Carvalho, Bradley Spencer-Dene, Eleanor Herbert, Gordon Stamp, Djamil Damry, Dinis P. Calado, Ian Rosewell, Ralph Fritsch, Richard R. Neubig, Miriam Molina-Arcas, Julian Downward

Issue&Volume: Volume36 Issue1

Abstract: RAC1 P29 is the third most commonly mutated codon in human cutaneous melanoma, after BRAF V600 and NRAS Q61. Here, we study the role of RAC1P29S in melanoma development and reveal that RAC1P29S activates PAK, AKT, and a gene expression program initiated by the SRF/MRTF transcriptional pathway, which results in a melanocytic to mesenchymal phenotypic switch. Mice with ubiquitous expression of RAC1P29S from the endogenous locus develop lymphoma. When expressed only in melanocytes, RAC1P29S cooperates with oncogenic BRAF or with NF1-loss to promote tumorigenesis. RAC1P29S also drives resistance to BRAF inhibitors, which is reversed by SRF/MRTF inhibitors. These findings establish RAC1P29S as a promoter of melanoma initiation and mediator of therapy resistance, while identifying SRF/MRTF as a potential therapeutic target.

DOI: https://doi.org/10.1016/j.ccell.2019.05.015

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(19)30257-0