Gene expression profiling of oncogenic NRAS driven mouse melanomas that have developed resistance to NRAS withdrawal

ABSTRACT: 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. 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.

ORGANISM(S): Mus musculus

SUBMITTER: Guo Chen 

PROVIDER: E-GEOD-51906 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress