Author:
Su Yapeng,Lu Xiang,Li Guideng,Liu Chunmei,Kong Yan,Lee Jihoon W.,Ng Rachel,Wong Stephanie,Robert Lidia,Warden Charles,Liu Victoria,Chen Jie,Wang Zhuo,Yang Yezi,Cheng Hanjun,Ng Alphonsus H. C.,Qin Guangrong,Peng Songming,Xue Min,Johnson Dazy,Xu Yu,Wang Jinhui,Wu Xiwei,Shmulevich Ilya,Shi Qihui,Levine Raphael,Ribas Antoni,Baltimore David,Guo Jun,Heath James R.,Wei Wei
Abstract
SummaryWe resolved a mechanism connecting tumor epigenetic plasticity with non-genetic adaptive resistance to therapy, with MAPK inhibition ofBRAF-mutant melanomas providing the model. These cancer cells undergo multiple, reversible drug-induced cell-state transitions, ultimately yielding a drug-resistant mesenchymal-like phenotype. A kinetic series of transcriptome and epigenome data, collected over two months of drug treatment and release, revealed changing levels of thousands of genes and extensive chromatin remodeling. However, a 3-step computational algorithm greatly simplified the interpretation of these changes, and revealed that the whole adaptive process was controlled by a gene module activated within just three days of treatment, with RelA driving chromatin remodeling to establish an epigenetic program encoding long-term phenotype changes. These findings were confirmed across several patient-derived cell lines and in melanoma patients under MAPK inhibitor treatment. Co-targeting BRAF and histone-modifying enzymes arrests adaptive transitions towards drug tolerance in epigenetically plastic melanoma cells and may be exploited therapeutically.
Publisher
Cold Spring Harbor Laboratory