| Summary: | 碩士 === 國立臺灣大學 === 生化科學研究所 === 106 === Afatinib (BIBW 2992, Gilotrif™, Giotrif®) is a drug developed by Boehringer Ingelheim to treat non-small cell lung cancer as targeted therapy. Afatinib can act as an irreversible covalent inhibitor of the tyrosine kinases in the ErbB family (EGFR, HER2, HER4), which control cell signaling for cell survival, proliferation and metastasis. The advantage of afatinib is that it can overcome drug resistance mutation (T790M and L858R) induced by the noncovalent non-small lung cancer drugs (erlotinib and gefitinib) and extend the survival time of drug-resistant patients. Our laboratory previously has developed a drug target identification method (TISTA) and found that afatinib can not only target EGFR but also inhibit ribonucleotide reductase (RNR) as a direct target. This finding can serve as a foundation for further research on drug indications and combination therapy using afatinib. In this study, from a list of potential target proteins of afatinib, we selected four enzymes that have similar functions to RNR in nucleotide metabolism. These potential target proteins are DTYMK, ADSL, Nm23-H1/H2/H3, and GMPS. We aimed to investigate whether or not they are truly target proteins for afatinib. The results showed that the degradation of thymidylate kinase (DTYMK), adenylosuccinate lyase (ADSL), nucleoside diphosphate kinase (Nm23-H1/H2/H3) and GMP synthase (GMPS) in cells occurred when the cells were treated with 10 μM afatinib. However, when the cells were treated with lower concentrations of afatinib, these proteins accumulated, due to increased protein synthesis (DTYMK, ADSL and GMPS) or decreased protein degradation (Nm23-H1/H2/H3). Using various protein degradation inhibitors, it was found that DTYMK and Nm23-H1/H2/H3 degradation was mediated by lysosomal pathways. In conclusion, afatinib does affect these four proteins and has great potential for treating diseases caused by changes in these four proteins.
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