Exosomes derived from MDR cells induce cetuximab resistance in CRC via PI3K/AKT signaling‑mediated Sox2 and PD‑L1 expression

The anti-EGFR antibody cetuximab is used as a first-line targeted therapeutic drug in colorectal cancer. It has previously been reported that the efficacy of the EGFR antibody cetuximab is limited by the emergence of acquired drug resistance. In our previous study the transmissibility effect of exosomes from drug resistant tumor cells to sensitive tumor cells was identified. It can therefore be hypothesized that drug resistant cells might affect neighboring and distant cells via regulation of exosome composition and behavior. However, the mechanism of exosomes in KRAS-wild-type colorectal cancer (CRC) remains unknown. In the present study, functional analysis of overall survival post-diagnosis in patients with KRAS wild-type and those with mutant CRC was performed using human CRC specimens. Furthermore, it was demonstrated that multidrug resistance (MDR) cancer cell-derived exosomes were potentially a key factor, which promoted cetuximab-resistance in CRC cells and reduced the inhibitory effect of cetuximab in CRC xenograft models. The Cell Counting Kit-8 and colony formation assays were performed to assess the effects of exosomes derived from CRC/MDR cells on cetuximab resistance. Sphere formation assay results demonstrated that exosomes derived from CRC/MDR cells altered the self-renewal and multipotential ability of stem-cell-associated markers and facilitated resistance to cetuximab in cetuximab-sensitive cells. Furthermore, exosomes derived from CRC/MDR cells decreased sensitivity to cetuximab via the activation of PI3K/AKT signaling, which promoted Sox2 and programmed death-ligand 1 (PD-L1) mRNA and protein expression according to reverse transcription-quantitative PCR, western blotting and immunohistochemistry analyses, as well as apoptosis resistance both in vitro and in vivo according to a TUNEL assay. In conclusion, the results of the present study demonstrated that exosomes derived from CRC/MDR cells may promote cetuximab resistance in KRAS wild-type cells via activation of the PI3K/AKT signaling pathway-mediated expression of Sox2 and PD-L1, which will be useful for investigating a potential clinical target in predicting cetuximab resistance.