T790M
外观
T790M ,也称为Thr790Met ,是一种发生在表皮生长因子受体(EGFR)基因上的看守突变(gatekeeper mutation)。这个突变发生在EGFR基因的第20个外显子上、第790个位点的苏胺酸(T)被甲硫胺酸(M)所取代,[1]因此影响了EGFR激酶区的ATP结合囊袋。苏胺酸是具极性的小型氨基酸;而甲硫胺酸则是非极性的较大氨基酸。T790M借由增加ATP与EGFR上的活性位之间的亲和力(而非直接阻碍抑制剂与活性位结合),使ATP比抑制剂更具有与活性位结合的优势。然而,共价抑制剂(covalent inhibitors),例如neratinib,可以克服此一抗药性。[2]
临床
[编辑]EGFR酪胺酸激酶抑制剂的继发抗药性(acquired resistance),有一半以上是由于EGFR激酶区的ATP结合囊袋上发生了突变所引起的;这种突变涉及T790M,使小型具极性的苏胺酸被较大的非极性甲硫胺酸所取代。[3][4]
2015年11月,奥希替尼(Tagrisso) 获得美国食品药品监督管理局(FDA)的加速批准,用以治疗在接受EGFR抑制剂治疗的同时或之后发展出的转移性非小细胞肺癌,这种肺癌须带有以FDA批准的方法检测而得的EGFR T790M突变。[5][6]
参考文献
[编辑]- ^ 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).
- ^ 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
. PMID 18227510. doi:10.1073/pnas.0709662105.
- ^ 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.
- ^ 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.
- ^ U.S. Food and Drug Administration. Hematology/Oncology (Cancer) Approvals & Safety Notifications.
- ^ 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.