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

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.

Chemotherapy combined with target drugs in the treatment of advanced colorectal cancer: A meta-analysis based on Chinese patients.

BACKGROUND: Colorectal carcinoma is one of most diagnosed solid malignant carcinoma. The chemotherapy combined with target drugs in the treatment of advanced colorectal cancer in not conclusive. METHODS: The clinical studies reporting the activity and adverse events between chemotherapy alone versus chemotherapy combined with anti‑epidermal growth factor receptor drugs were screened in the databases of Medline, the Cochrane Library, Wanfang and CNKI and included in this meta‑analysis. The risk ratio (RR) and its 95% confidence interval (CI) for treatment response and adverse events were pooled by random or fixed effect model. RESULTS: A total of 10 clinical studies reporting chemotherapy combined with the target in the treatment of advanced colorectal cancer were included in this study. The pooled RR was 3.26 (95% CI: 1.74–6.11, P < 0.05), 1.49 (95% CI: 1.23–1.80) and 1.65 (95% CI: 1.37–1.98) for complete response (CR), partial response and objective response rate, respectively. For nausea and vomiting events, the RR was 1.62 (95% CI: 1.33–1.97, P < 0.05) indicating higher incidence of nausea and vomiting was observed in the combined group compared with chemotherapy alone. However, the diarrhea (RR = 1.10, 95% CI: 0.86–1.42, P > 0.05), liver function damage (RR = 1.03, 95% CI: 0.74–1.42), myelosuppression (RR = 1.04, 95% CI: 0.83–1.31) and neurotoxicity (RR = 1.12, 95% CI: 0.93–1.35) were not different between the two groups. CONCLUSION: For Chinese patients with advanced colorectal cancer, chemotherapy combined with target drug can improve the response rate, but also increase the risk of nausea and vomiting.