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

Abstract

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.

Dysregulated Signalling Pathways Driving Anticancer Drug Resistance

“…Exosomal miR-21 and IL-6 produced from CAFs together increased MDSC formation in oesophageal squamous cell carcinoma by activating STAT3, which made tumour cells resistant to cisplatin [234]. Furthermore, SOX2 and PD-L1 expression was mediated by PI3K/Akt signalling pathway activation and was shown to be a mechanism by which exosomes from CRC/MDR cells may increase cetuximab resistance in KRAS wild-type cells [235].…”

The Impact of Cancer Stem Cells in Colorectal Cancer

“…By characterizing these exosomes and elucidating their role in mediating drug resistance, they provided valuable insights into potential therapeutic targets. Furthermore, their findings underscored the involvement of the PI3K/AKT signaling pathway and stem cell-associated genes in promoting cetuximab resistance, highlighting the complexity of CRC resistance mechanisms [96].…”

Exosomes in Cancer Progression and Therapy Resistance: Molecular Insights and Therapeutic Opportunities

“…In a colon cancer model, exosomes could transfer cetuximab resistance to sensitive cells by downregulating PTEN and increasing p-Akt levels [226]. Another study found that exosomes released from MDR colorectal cancer cells increased PD-L1 and Sox2 expression in recipient cells via PI3K/AKT activation and led to the expression of stem-cell-associated markers, resulting in cetuximab resistance [227]. Bevacizumabresistant colorectal cancer cells and their respective exosomes carry increased levels of the lncRNA SNHG11.…”