In addition, inhibition of RSK2 or PAK4 enhances 5‐FU‐triggered colorectal cancer cell apoptosis (Figure 4), which is consistent with the finding that RSK2 knockdown induces apoptosis in human myeloma cells.[32] Considering the role of EGFR/PAK2/ERK5 signaling axis in resistance to lenvatinib and the role of RSK2 in EGF‐activated histone H3 phosphorylation and inactive ERK binding to RSK2,[31, 42] we postulate that RSK2/TP53BP1/γ‐H2AX and PAK4/ERK may confer to 5‐FU chemoresistance through a same signaling pathway or an integrated interaction network. This evidence concerns the gene RPS6KA3 and colorectal cancer.