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Series GSE51906 Query DataSets for GSE51906
Status Public on Oct 31, 2014
Title Gene expression profiling of oncogenic NRAS driven mouse melanomas that have developed resistance to NRAS withdrawal
Organism Mus musculus
Experiment type Expression profiling by array
Summary Targeted therapies have the potential to revolutionize cancer care by providing personalized treatment strategies that are less toxic and more effective but it is clear that for most solid tumors suppression of a single target is not sufficient to prevent development of resistance. A powerful method to identify mechanisms of resistance and targets for combination therapy is to use an in vivo genetic approach. We have developed a novel retroviral gene delivery mouse model of melanoma that permits control of gene expression post-delivery using the tetracycline (tet)-regulated system. In this study we used this melanoma model to select for resistant tumors following genetic inhibition of mutant NRAS. Analysis of tumors that became resistant to NRAS suppression revealed that the most common mechanism of resistance was overexpression of the Met receptor tyrosine kinase (RTK). Importantly, inhibition of Met overcomes NRAS resistance in this context. Analysis of NRAS mutant human melanoma cells revealed that inhibition of MEK is also associated with adaptive RTK signaling. Furthermore, co-inhibition of RTK signaling and MEK overcomes acquired MEK inhibitor resistance in NRAS mutant melanoma. These data suggest that combined inhibition of RTK and MEK signaling is a rational therapeutic strategy in mutant NRAS driven melanoma.
 
Overall design Reversible NRAS Q61R expression in the melanocytes of DCT-TVA;Ink4a/Arf lox/lox mice (FVB/n) was achieved by transducing the animals with Tet-off and TRE-NRASQ61R-IRES-Cre avian leukosis viruses. After tumor initiation, the expression of NRAS Q61R was turned off by administrating doxycycline. Despite initial regression, tumors in 40% of mice developed resistance to NRAS Q61R withdraw. Seven resistant tumors and one control tumor where NRAS Q61R expression was not interrupted were subjected to genome-wide gene expression profiling.
 
Contributor(s) Rebecca VW, Robinson JP, Fedorenko IV, Gibney GT, Messina JL, Lastwika KJ, Grossman D, Chen G, Davies M, VanBrocklin MW, Smalley KM, Holmen SL
Citation(s) 29076949
Submission date Oct 30, 2013
Last update date Jul 19, 2019
Contact name Guo Chen
Phone 713-792-8603
Organization name The University of Texas MD Anderson Cancer Center
Department Melanoma Medical Oncology
Lab Michael A. Davies
Street address 7435 Fannin Street
City Houston
State/province TX
ZIP/Postal code 77054
Country USA
 
Platforms (1)
GPL6885 Illumina MouseRef-8 v2.0 expression beadchip
Samples (8)
GSM1254887 NRASQ61R_control_tumor
GSM1254888 NRASQ61R_off_resistant_tumor_1
GSM1254889 NRASQ61R_off_resistant_tumor_2
Relations
BioProject PRJNA225793

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE51906_RAW.tar 3.1 Mb (http)(custom) TAR
GSE51906_non-normalized.txt.gz 871.2 Kb (ftp)(http) TXT
Raw data are available on Series record
Processed data included within Sample table

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