Collectively, these data suggest that RSK2 or PAK4 phosphorylation mediates resistance to 5‐FU chemotherapy and that suppression of RSK2 or PAK4 activation in combination with 5‐FU displays a synergistic inhibitory effect on cell growth and apoptosis in colorectal cancer cells, involving ERK and P53 signaling pathways (Figure S13C, Supporting Information). This evidence concerns the gene RPS6KA3 and colorectal cancer.