Exosomes promote cetuximab resistance via the PTEN/Akt pathway in colon cancer cells

Abstract

Cetuximab is widely used in patients with metastatic colon cancer expressing wildtype KRAS. However, acquired drug resistance limits its clinical efficacy. Exosomes are nanosized vesicles secreted by various cell types. Tumor cell-derived exosomes participate in many biological processes, including tumor invasion, metastasis, and drug resistance. In this study, exosomes derived from cetuximab-resistant RKO colon cancer cells induced cetuximab resistance in cetuximab-sensitive Caco-2 cells. Meanwhile, exosomes from RKO and Caco-2 cells showed different levels of phosphatase and tensin homolog (PTEN) and phosphor-Akt. Furthermore, reduced PTEN and increased phosphorylated Akt levels were found in Caco-2 cells after exposure to RKO cell-derived exosomes. Moreover, an Akt inhibitor prevented RKO cell-derived exosome-induced drug resistance in Caco-2 cells. These findings provide novel evidence that exosomes derived from cetuximab-resistant cells could induce cetuximab resistance in cetuximab-sensitive cells, by downregulating PTEN and increasing phosphorylated Akt levels.

Extracellular vesicles as circulating cancer biomarkers: opportunities and challenges

“…Tumour-derived EVs have been implicated in resistance to numerous therapeutics by mediating the transfer of specific miRNA and/or protein species from drug-resistant to drug-sensitive cells. This phenomenon has been demonstrated across several cancer types and therapies including Tamoxifen (anti-estrogen) [ 72 ] therapies in breast cancer, Cetuximab (anti-EGFR) therapy in colon cancer [ 73 ] and Pazopanib (chemotherapy) in soft tissue sarcoma [ 74 ]. In these studies, exposure to EVs from resistant cells was demonstrated to disrupt drug-associated signalling pathways in sensitive recipients, and this is proposed to contribute to the development of resistance.…”

The role of extracellular vesicles in acquisition of resistance to therapy in glioblastomas

“…Multiple studies across several systemic cancers have shown that EV-mediated transfer of functional cargo (mRNAs, miRNAs, long non-coding RNA (lncRNA), and proteins) induces drug resistance in drugsensitive cancer cells [76] . The transferred functional molecules upsurge drug efflux [77][78][79][80] , enhance drug metabolism/inactivation [81] , activate anti-apoptotic and tumor-promoting pathways [82][83][84][85][86][87][88] , elicit downstream changes in signal transduction and gene expression [89][90][91][92][93][94][95] , and promote epithelial-to-mesenchymal transition [96][97][98][99] to favor a resistant phenotype. GBM cells actively modulate the composition of EVs in response to chemotherapy and radiation [100,101] .…”

The immunomodulatory role of tumor‐derived extracellular vesicles in colorectal cancer

“…In contrast to their use as immune‐stimulators, tEVs are also capable of aiding tumor in the circumvention of immunotherapies. Cetuximab is a recombinant epidermal growth factor receptor monoclonal antibody that is now used clinically in the treatment of several cancers . It may be used as a therapeutic agent in addition to other chemotherapy drugs for example, irinocetan, for some patients with metastatic CRC and previously was shown to improve clinical outcomes of CRC patients with wild‐type KRAS.…”

“…However, a subset of patients with wild‐type KRAS still derives no benefit from Cetuximab treatment and acquired drug resistance limits its utility. A recent study has reported that Cetuximab‐resistant CRC cells are capable of inducing resistance in Cetuximab‐sensitive cells, and that this effect is mediated by tEVs . This suggests that targeting of tEVs could be beneficial in preventing drug resistance in the future.…”