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T790M

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T790M ,也稱為Thr790Met ,是一種發生在表皮生長因子受體(EGFR)基因上的看守突變(gatekeeper mutation)。這個突變發生在EGFR基因的第20個外顯子上、第790個位點的蘇胺酸(T)被甲硫胺酸(M)所取代,[1]因此影響了EGFR激酶區的ATP結合囊袋。蘇胺酸是具極性的小型胺基酸;而甲硫胺酸則是非極性的較大胺基酸。T790M藉由增加ATP與EGFR上的活性位之間的親和力(而非直接阻礙抑制劑與活性位結合),使ATP比抑制劑更具有與活性位結合的優勢。然而,共價抑制劑(covalent inhibitors),例如neratinib英语neratinib,可以克服此一抗藥性。[2]

臨床

EGFR酪胺酸激酶抑制劑的繼發抗藥性(acquired resistance),有一半以上是由於EGFR激酶區的ATP結合囊袋上發生了突變所引起的;這種突變涉及T790M,使小型具極性的蘇胺酸被較大的非極性甲硫胺酸所取代。[3][4]


2015年11月,奧希替尼(Tagrisso) 獲得美國食品藥品監督管理局(FDA)的加速批准,用以治療在接受EGFR抑制劑治療的同時或之後發展出的轉移性非小細胞肺癌英语Non-small cell lung cancer,這種肺癌須帶有以FDA批准的方法檢測而得的EGFR T790M突變。[5][6]

參考文獻

  1. ^ Tan CS, Gilligan D, Pacey S. Treatment approaches for EGFR-inhibitor-resistant patients with non-small-cell lung cancer. Lancet Oncol. 2015, 16 (9): e447–59 [2020-11-30]. PMID 26370354. doi:10.1016/S1470-2045(15)00246-6. (原始内容存档于2020-07-17). 
  2. ^ Yun, CH; Mengwasser, KE; Toms, AV; Woo, MS; Greulich, H; Wong, KK; Meyerson, M; Eck, MJ. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP.. Proceedings of the National Academy of Sciences of the United States of America. 12 February 2008, 105 (6): 2070–5. PMC 2538882可免费查阅. PMID 18227510. doi:10.1073/pnas.0709662105. 
  3. ^ Remon J, Planchard D. AZD9291 in EGFR-mutant advanced non-small-cell lung cancer patients. Future Oncol. 2015, 11 (22): 3069–81. PMID 26450446. doi:10.2217/fon.15.250. 
  4. ^ Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clin Cancer Res. 2006, 12 (1): 6494–501. PMID 17085664. doi:10.1158/1078-0432.CCR-06-1570. 
  5. ^ U.S. Food and Drug Administration. Hematology/Oncology (Cancer) Approvals & Safety Notifications.
  6. ^ Inal C, Yilmaz E, Piperdi B, Perez-Soler R, Cheng H. Emerging treatment for advanced lung cancer with EGFR mutation. Expert Opin Emerg Drugs. 2015, 20 (4): 1–16. PMID 26153235. doi:10.1517/14728214.2015.1058778.