Recently, it has been reported that feedback activation of the EGFR/PAK2/ERK5 signaling limits the sensitivity of liver cancer cells to lenvatinib chemotherapy.[31] Coincidently, FGFR3 activates RSK2 through tyrosine 529 phosphorylation of RSK2 to activate MEK/ERK pathway during hematopoietic transformation (Figure 4B).[32] We propose that RSK2 and PAK4 may integrate at the TP53[33] and ERK pathway[34] to mediate 5‐FU chemoresistance. Here, PAK4 is linked to liver cancer.