Abstract
<div>Abstract<p><b>Purpose:</b> Effective therapies for <i>KRAS</i>-mutant colorectal cancer (CRC) are a critical unmet clinical need. Previously, we described genetically engineered mouse models (GEMM) for sporadic <i>Kras</i>-mutant and non-mutant CRC suitable for preclinical evaluation of experimental therapeutics. To accelerate drug discovery and validation, we sought to derive low-passage cell lines from GEMM <i>Kras</i>-mutant and wild-type tumors for <i>in vitro</i> screening and transplantation into the native colonic environment of immunocompetent mice for <i>in vivo</i> validation.</p><p><b>Experimental Design:</b> Cell lines were derived from <i>Kras</i>-mutant and non-mutant GEMM tumors under defined media conditions. Growth kinetics, phosphoproteomes, transcriptomes, drug sensitivity, and metabolism were examined. Cell lines were implanted in mice and monitored for <i>in vivo</i> tumor analysis.</p><p><b>Results:</b><i>Kras</i>-mutant cell lines displayed increased proliferation, mitogen-activated protein kinase signaling, and phosphoinositide-3 kinase signaling. Microarray analysis identified significant overlap with human CRC-related gene signatures, including <i>KRAS</i>-mutant and metastatic CRC. Further analyses revealed enrichment for numerous disease-relevant biologic pathways, including glucose metabolism. Functional assessment <i>in vitro</i> and <i>in vivo</i> validated this finding and highlighted the dependence of <i>Kras</i>-mutant CRC on oncogenic signaling and on aerobic glycolysis.</p><p><b>Conclusions:</b> We have successfully characterized a novel GEMM-derived orthotopic transplant model of human <i>KRAS</i>-mutant CRC. This approach combines <i>in vitro</i> screening capability using low-passage cell lines that recapitulate human CRC and potential for rapid <i>in vivo</i> validation using cell line-derived tumors that develop in the colonic microenvironment of immunocompetent animals. Taken together, this platform is a clear advancement in preclinical CRC models for comprehensive drug discovery and validation efforts. <i>Clin Cancer Res; 19(11); 2929–40. ©2013 AACR</i>.</p></div>
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