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.
Highlights
Colon cancer is the third most commonly diagnosed malignancy worldwide [1]
These results indicated that RKO cells were resistant to cetuximab, unlike Caco-2 cells, which were cetuximab-sensitive
Co-culture of Caco-2 cells with RKO cell-derived exosomes (20 or 50 mg/mL) for 48 h resulted in decreased phosphatase and tensin homolog (PTEN) levels and increased Akt phosphorylation (Figure 3D). These findings suggested that RKOderived exosomes decreased cetuximab sensitivity in Caco-2 cells through PTEN downregulation and Akt phosphorylation
Summary
Colon cancer is the third most commonly diagnosed malignancy worldwide [1]. Radical surgery is an effective therapeutic approach for non-metastatic colon cancer. The prognosis of patients with metastatic colon cancer remains very poor. Cetuximab (C225), a chimeric human-mouse anti-epidermal growth factor receptor (EGFR) monoclonal antibody, can improve clinical outcomes in some patients with metastatic colon cancer expressing wild type KRAS. Only a subgroup of individuals with KRAS wildtype cancer benefit from C225 treatment, suggesting the existence of other drug resistance mechanisms, in addition to KRAS gene mutation [2,3]. Recent studies indicated that primary and acquired drug resistance induced by aberrant mutations in oncogenes or tumor suppressor genes could reduce C225 efficacy in some patients [4,5,6,7]. Cell-cell communication within the tumor microenvironment is another potential mechanism of acquired drug resistance. How drug resistance information is exchanged between cells is largely unclear
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