IPO5 contributes to cetuximab resistance in colorectal cancer by modulating Ras signaling

Resistance to cetuximab is a major challenge in colorectal cancer (CRC). Here, we show that IPO5, an importin mediating RASAL2 nuclear import, contributes to cetuximab resistance. Screening six CRC cell lines revealed an inverse correlation between IPO5 expression and cetuximab sensitivity, with higher IPO5 levels in resistant (RKO and SW620) than sensitive (LoVo and Caco2) cells. IPO5 knockdown in resistant cells restored cetuximab sensitivity, induced apoptosis (upregulated active caspase-3/BAX and downregulated BCL-2), and suppressed proliferation and xenograft growth, whereas IPO5 overexpression in sensitive cells reduced sensitivity. Mechanistically, IPO5 facilitates RASAL2 nuclear translocation via its nuclear localization signal, depleting cytoplasmic RASAL2 and increasing GTP-bound RAS to sustain AKT and MAPK activation. Consistently, IPO5 and downstream Ras effectors were elevated in resistant LoVo-CR cells. Collectively, our findings identify the IPO5/RASAL2 axis as a key contributor to cetuximab resistance in CRC by disrupting the cytoplasmic localization of RASAL2 and activating the RAS/MAPK and PI3K/AKT pathways.