Acquired rare recurrent EGFR mutations as mechanisms of resistance to Osimertinib in lung cancer and in silico structural modelling.

Autor:	Lin L; Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing, China., Lu Q; Department of Thoracic Surgery, Tangdu Hospital, The Air Force Military Medical University Xi'an, Shaanxi, China., Cao R; Translational Medicine Research Institute, Geneseeq Technology Inc. Toronto, ON, Canada., Ou Q; Translational Medicine Research Institute, Geneseeq Technology Inc. Toronto, ON, Canada., Ma Y; Translational Medicine Research Institute, Geneseeq Technology Inc. Toronto, ON, Canada., Bao H; Translational Medicine Research Institute, Geneseeq Technology Inc. Toronto, ON, Canada., Wu X; Translational Medicine Research Institute, Geneseeq Technology Inc. Toronto, ON, Canada., Shao Y; Nanjing Geneseeq Technology Inc. Nanjing, Jiangsu, China.; School of Public Health, Nanjing Medical University Nanjing, Jiangsu, China., Wang Z; Department of Oncology, The Second Affiliated Hospital of Nanjing Medical University Nanjing, Jiangsu, China., Shen B; Department of Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital Nanjing, Jiangsu, China.
Jazyk:	angličtina
Zdroj:	American journal of cancer research [Am J Cancer Res] 2020 Nov 01; Vol. 10 (11), pp. 4005-4015. Date of Electronic Publication: 2020 Nov 01 (Print Publication: 2020).
Abstrakt:	A growing number of progression on Osimertinib among EGFR -mutated lung cancers represents a great challenge clinically. Our study aims to gain insights into novel mechanisms of acquired resistance to Osimertinib. We performed genomic studies on 2 large independent cohorts of lung cancer patients with progressed diseases on different tyrosine kinase inhibitors (TKIs). In silico modeling was used to study the structural mechanism of selected EGFR mutations. Compared with the 1 st -TKIs-resistant group, EGFR mutations C797S/G, L718Q/V, L792F/H were significantly more enriched in the Osimertinib-resistant cohort, whose sensitivities to Osimertinib were successfully predicted. Importantly, a total of 14 low-frequency EGFR mutations were exclusively or significantly observed in the Osimertinib-resistant group, 7 were predicted to dramatically reduce the binding affinity of EGFR to Osimertinib (G796S, V802F, T725M, Q791L/H, P794S/R). Analysis of pre-Osimertinib treatment samples of two patients supported that EGFR V802F and G796S were acquired during the treatment. In addition, EGFR G796S was predicted to be susceptible to gefitinib. This study represented the largest real-world data so far investigating Osimertinib resistance in EGFR -mutated lung cancer. We identified a collection of coexistent EGFR rare mutations and provided possible guidance for those patients who progressed on the first-line treatment of Osimertinib. Competing Interests: Ran Cao, Qiuxiang Ou, Yutong Ma, Hua Bao, and Xue Wu are employees of Geneseeq Technology Inc., Toronto, Canada. Yang Shao is an employee of Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu, China. (AJCR Copyright © 2020.)
Databáze:	MEDLINE
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