Background: Although CRC is rare in young adults, the incidence has increased recently and patients present more commonly with Stage III or IV disease which may reflect differing biology. Prior analyses revealed a statistically significant increase in the risk of death in young patients with metastatic CRC compared to older patients. Methods: To assess age-dependent genetic changes, DNA and RNA from younger ( < 40) and older ( > 65) CRC were isolated, and whole exome and transcriptome sequencing analysis from 4699 FFPE CRC clinical specimens were performed. Hybridization capture was performed on up to 3,769 exons from 403 cancer-related genes and 47 introns of 19 genes commonly rearranged in cancer. Samples were sequenced to high (average 688X) uniform coverage. CRC PDXs were injected into athymic nude mice and randomized into vehicle control, refametinib (MEKi), OMP-18R5 (monoclonal Ab against FZD 1, 2, 5, 7, and 8), or the combination and treated for at least 28 days. Results: Gene alteration rates in the younger and older cohorts were similar in a majority of the genes analyzed. Alterations in CTNNB1 [p < 0.001, False Discovery Rate (FDR) = 0.07] and MLH1 (p < 0.001, FDR = 0.017) were found to be more common in younger patients. Older patients were more likely to have alterations in APC (p < 0.01, FDR < 0.01) and FAM123B (p < 0.01, FDR = 0.03). The CTNNB1 data provided support to explore the WNT pathway as a potential target for younger patients. Therefore, we conducted an in vivo study of MEKi and OMP-18R5 to assess efficacy in molecularly defined young CRC PDX models. In a young PDX models, we observed enhanced combination effects with tumor growth inhibition index (treated/control) of 13% in the combination arm (compared to tumor growth of 150 %, and 116%, respectively with MEKi and OMP-18R5 alone). Interestingly, in this PDX models, RNA sequencing data showed baseline enrichment in the WNT and mTOR pathway, not observed in the older PDX models. Conclusions: The combination of refametinib and OMP-18R5 showed enhanced antitumor activity in combination compared to the single agent arms. Studies investigating predictive biomarkers of response are currently underway.