1. Selumetinib overcomes ITGA2-induced 5-fluorouracil resistance in colorectal cancer.
- Author
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Qin J, Hu S, Lou J, Xu M, Gao R, Xiao Q, Chen Y, Ding M, Pan Y, and Wang S
- Subjects
- Humans, Animals, Cell Line, Tumor, Mice, Gene Expression Regulation, Neoplastic drug effects, Mice, Nude, Xenograft Model Antitumor Assays, Mice, Inbred BALB C, Drug Resistance, Neoplasm genetics, Drug Resistance, Neoplasm drug effects, Fluorouracil therapeutic use, Fluorouracil pharmacology, Colorectal Neoplasms drug therapy, Colorectal Neoplasms genetics, Integrin alpha2 genetics, Integrin alpha2 metabolism, Benzimidazoles therapeutic use, Benzimidazoles pharmacology
- Abstract
Background: Colorectal cancer (CRC) is the third most malignant tumor in the world. 5-fluorouracil (5‑FU) -based chemotherapy is the first-line chemotherapy scheme for CRC, whereas acquired drug resistance poses a huge obstacle to curing CRC patients and the mechanism is still obscure. Therefore, identification of genes associated with 5‑FU chemotherapy and seeking second-line treatment are necessary means to improve survival and prognosis of patients with CRC., Methods: The Cancer Therapeutics Response Portal (CTRP) database and Genomics of Drug Sensitivity in Cancer (GDSC) database were used to identify CRC-related genes and potential second-line therapies for 5-FU-resistant CRC. The single-cell RNA sequencing data for CRC tissues were obtained from a GEO dataset. The relationship between ITGA2 and 5-FU-resistant was investigated in vitro and in vivo models., Results: ACOX1 and ITGA2 were identified as risk biomarkers associated with 5-FU-resistance. We developed a risk signature, consisting of ACOX1 and ITGA2, that was able to distinguish well between 5-FU-resistance and 5-FU-sensitive. The single-cell sequencing data showed that ITGA2 was mainly enriched in malignant cells. ITGA2 was negatively correlated with IC50 values of most small molecule inhibitors, of which selumetinib had the highest negative correlation. Finally, knocking down ITGA2 can make 5-FU-resistant CRC cells sensitive to 5-FU and combining with selumetinib can improve the therapeutic effect of 5-FU resistant cells., Conclusion: In summary, our findings demonstrated the critical role of ITGA2 in enhancing chemotherapy resistance in CRC cells and suggested that selumetinib can restore the sensitivity of chemotherapy-resistant CRC cells to 5-FU by inhibiting ITGA2 expression., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)
- Published
- 2024
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