Upregulation of IGF1R by mutant RAS in leukemia and potentiation of RAS signaling inhibitors by small-molecule inhibition of IGF1R.

ABSTRACT:

Purpose

Activating mutations in the RAS oncogene occur frequently in human leukemias. Direct targeting of RAS has proven to be challenging, although targeting of downstream RAS mediators, such as MEK, is currently being tested clinically. Given the complexity of RAS signaling, it is likely that combinations of targeted agents will be more effective than single agents.

Experimental design

A chemical screen using RAS-dependent leukemia cells was developed to identify compounds with unanticipated activity in the presence of an MEK inhibitor and led to identification of inhibitors of IGF1R. Results were validated using cell-based proliferation, apoptosis, cell-cycle, and gene knockdown assays; immunoprecipitation and immunoblotting; and a noninvasive in vivo bioluminescence mode

SUBMITTER: Weisberg E 

PROVIDER: S-EPMC4216757 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature