TY  - JOUR
A1  - Webster, Dan E.
A1  - Barajas, Brook
A1  - Bussat, Rose T.
A1  - Yan, Karen J.
A1  - Neela, Poornima H.
A1  - Flockhart, Ross J.
A1  - Kovalski, Joanna
A1  - Zehnder, Ashley
A1  - Khavari, Paul A.
T1  - Enhancer-targeted genome editing selectively blocks innate resistance to oncokinase inhibition
Y1  - 2014/05/01 
JF  - Genome Research 
JO  - Genome Research 
SP  - 751 
EP  - 760 
DO  - 10.1101/gr.166231.113 
VL  - 24 
IS  - 5 
UR  - http://genome.cshlp.org/content/24/5/751.abstract 
N2  - Thousands of putative enhancers are characterized in the human genome, yet few have been shown to have a functional role in cancer progression. Inhibiting oncokinases, such as EGFR, ALK, ERBB2, and BRAF, is a mainstay of current cancer therapy but is hindered by innate drug resistance mediated by up-regulation of the HGF receptor, MET. The mechanisms mediating such genomic responses to targeted therapy are unknown. Here, we identify lineage-specific enhancers at the MET locus for multiple common tumor types, including a melanoma lineage-specific enhancer 63 kb downstream from the MET TSS. This enhancer displays inducible chromatin looping with the MET promoter to up-regulate MET expression upon BRAF inhibition. Epigenomic analysis demonstrated that the melanocyte-specific transcription factor, MITF, mediates this enhancer function. Targeted genomic deletion (<7 bp) of the MITF motif within the MET enhancer suppressed inducible chromatin looping and innate drug resistance, while maintaining MITF-dependent, inhibitor-induced melanoma cell differentiation. Epigenomic analysis can thus guide functional disruption of regulatory DNA to decouple pro- and anti-oncogenic functions of a dominant transcription factor and block innate resistance to oncokinase therapy. 
ER  -