期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：50
页码：14402-14407
DOI：10.1073/pnas.1611106113
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceMutations in BRAF are dominant drivers of melanoma, and hence targeting them has been a success story in treatment of cancer. However, resistance to BRAF inhibitors is rapidly acquired and is a major impediment to cancer therapy. BRAF mutations per se only lead to nevi that remain nonmalignant for decades. What then is the key rate-limiting determinant of BRAF signaling for progression to melanomas? We show that mutant TERT promoter is a key downstream target of RAS-ERK and its activation downstream of BRAF signaling is a major rate-limiting step in melanoma progression, suggesting that simultaneous disruption of BRAF signaling and active chromatin remodeling at mutant TERT promoters may be an attractive strategy to overcome BRAF-inhibitor resistance during melanoma therapy. Although activating BRAF/NRAS mutations are frequently seen in melanomas, they are not sufficient to drive malignant transformation and require additional events. Frequent co-occurrence of mutations in the promoter for telomerase reverse transcriptase (TERT), along with BRAF alterations, has recently been noted and correlated with poorer prognosis, implicating a functional link between BRAF signaling and telomerase reactivation in melanomas. Here, we report that RAS-ERK signaling in BRAF mutant melanomas is critical for regulating active chromatin state and recruitment of RNA polymerase II at mutant TERT promoters. Our study provides evidence that the mutant TERT promoter is a key substrate downstream of the RAS-ERK pathway. Reactivating TERT and hence reconstituting telomerase is an important step in melanoma progression from nonmalignant nevi with BRAF mutations. Hence, combined targeting of RAS-ERK and TERT promoter remodeling is a promising avenue to limit long-term survival of a majority of melanomas that harbor these two mutations.
