Chemistry:T790M
T790M, also known as Thr790Met, is a gatekeeper mutation of the epidermal growth factor receptor (EGFR). The mutation substitutes a threonine (T) with a methionine (M) at position 790 of exon 20,[1] affecting the ATP binding pocket of the EGFR kinase domain. Threonine is a small polar amino acid; methionine is a larger nonpolar amino acid. Rather than directly blocking inhibitor binding to the active site, T790M increases the affinity for ATP so that the inhibitors are outcompeted; irreversible covalent inhibitors such as neratinib can overcome this resistance.[2] [3]
Clinical
Over 50% of acquired resistance to EGFR tyrosine kinase inhibitors (TKI) is caused by a mutation in the ATP binding pocket of the EGFR kinase domain involving substitution of a small polar threonine residue with a large nonpolar methionine residue, T790M.[4][5]
In November 2015, the US FDA granted accelerated approval to osimertinib (Tagrisso) for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC), as detected by an FDA-approved test, which progressed on or after EGFR TKI therapy.[6][7]
References
- ↑ "Treatment approaches for EGFR-inhibitor-resistant patients with non-small-cell lung cancer". Lancet Oncol. 16 (9): e447–59. 2015. doi:10.1016/S1470-2045(15)00246-6. PMID 26370354. https://www.repository.cam.ac.uk/handle/1810/252502.
- ↑ Yun, CH; Mengwasser, KE; Toms, AV; Woo, MS; Greulich, H; Wong, KK; Meyerson, M; Eck, MJ (12 February 2008). "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 105 (6): 2070–5. doi:10.1073/pnas.0709662105. PMID 18227510. Bibcode: 2008PNAS..105.2070Y.
- ↑ "The major lung cancer-derived mutants of ERBB2 are oncogenic and are associated with sensitivity to the irreversible EGFR/ERBB2 inhibitor HKI-272". Oncogene 26 (34): 5023–7. July 2007. doi:10.1038/sj.onc.1210292. PMID 17311002.
- ↑ "AZD9291 in EGFR-mutant advanced non-small-cell lung cancer patients". Future Oncol 11 (22): 3069–81. 2015. doi:10.2217/fon.15.250. PMID 26450446.
- ↑ "Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors". Clin Cancer Res 12 (1): 6494–501. 2006. doi:10.1158/1078-0432.CCR-06-1570. PMID 17085664.
- ↑ U.S. Food and Drug Administration. Hematology/Oncology (Cancer) Approvals & Safety Notifications. [1]
- ↑ "Emerging treatment for advanced lung cancer with EGFR mutation". Expert Opin Emerg Drugs 20 (4): 1–16. 2015. doi:10.1517/14728214.2015.1058778. PMID 26153235.
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