Qi Zhang1, Xu-Chao Zhang2, Jin-Ji Yang2, Zhen-Fan Yang3, Yu Bai3, Jian Su2, Zheng Wang4, Zhou Zhang5, Yang Shao6, Qing Zhou2, Jin Kang2, E-E Ke2, Yi-Chen Zhang2, Zhong-Yi Dong2, Zhi-Hong Chen2, Hai-Yan Tu2, Wen-Zhao Zhong2, Xue-Ning Yang2, Yi-Long Wu7. 1. Southern Medical University, Guangzhou, People's Republic of China; Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China. 2. Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China. 3. Dizal (Jiangsu) Pharmaceutical, Bioscience Wuxi, Jiangsu, People's Republic of China. 4. Asia Innovative Medicines and Early Development, AstraZeneca, Shanghai, People's Republic of China. 5. Burning Rock Biotech, Guangzhou, Guangdong Province, People's Republic of China. 6. Geneseeq Biotechnology, Inc., Nanjing, People's Republic of China. 7. Southern Medical University, Guangzhou, People's Republic of China; Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China. Electronic address: syylwu@live.cn.
Abstract
BACKGROUND: The third-generation EGFR tyrosine kinase inhibitor osimertinib has been approved in many countries to treat advanced NSCLC in patients with the EGFR T790M mutation. As the development of acquired resistance is inevitable, it is urgent that the mechanisms of such resistance be clarified. METHODS: DNA samples from a cohort of 340 patients with lung adenocarcinoma who were taking osimertinib were subjected to next-generation sequencing and screened in terms of the frequencies of the L792H and G796R mutations. Ba/F3 cells stably expressing the EGFR L858R/T790M mutations (in cis) with either the L792H or G796R mutation were created to investigate the impact of the two novel mutations on EGFR tyrosine kinase inhibitors and other potential drug combinations in vitro. Structural analyses were performed by using Schrödinger/Maestro software (version 11.1.012, Schrödinger LLC, Cambridge, MA). RESULTS: L792H and G796R were detected in 1.76% (six of 340) and 0.56% (two of 340) patients with lung adenocarcinoma treated with osimertinib, respectively. The introduction of L792H or G796R mutations against an L858R/T790M background caused dramatic reductions in osimertinib sensitivity. Structural modeling showed that mutations in cis with T790M either forced the ligand (osimertinib) to rotate out (breaking the binding) or pulled the hinge loop (breaking the hinge). Various other drug combinations. including cetuximab with EAI045, failed to inhibit either cis mutant effectively. CONCLUSIONS: The EGFR L858R/T790M/L792H and L858R/T790M/G796R mutations conferred resistance to osimertinib both in vitro and in silico. For patients in whom the two resistance mutations occur at low frequency, more precise treatment strategies and additional combinational approaches are required.
BACKGROUND: The third-generation EGFR tyrosine kinase inhibitor osimertinib has been approved in many countries to treat advanced NSCLC in patients with the EGFR T790M mutation. As the development of acquired resistance is inevitable, it is urgent that the mechanisms of such resistance be clarified. METHODS: DNA samples from a cohort of 340 patients with lung adenocarcinoma who were taking osimertinib were subjected to next-generation sequencing and screened in terms of the frequencies of the L792H and G796R mutations. Ba/F3 cells stably expressing the EGFR L858R/T790M mutations (in cis) with either the L792H or G796R mutation were created to investigate the impact of the two novel mutations on EGFR tyrosine kinase inhibitors and other potential drug combinations in vitro. Structural analyses were performed by using Schrödinger/Maestro software (version 11.1.012, Schrödinger LLC, Cambridge, MA). RESULTS: L792H and G796R were detected in 1.76% (six of 340) and 0.56% (two of 340) patients with lung adenocarcinoma treated with osimertinib, respectively. The introduction of L792H or G796R mutations against an L858R/T790M background caused dramatic reductions in osimertinib sensitivity. Structural modeling showed that mutations in cis with T790M either forced the ligand (osimertinib) to rotate out (breaking the binding) or pulled the hinge loop (breaking the hinge). Various other drug combinations. including cetuximab with EAI045, failed to inhibit either cis mutant effectively. CONCLUSIONS: The EGFR L858R/T790M/L792H and L858R/T790M/G796R mutations conferred resistance to osimertinib both in vitro and in silico. For patients in whom the two resistance mutations occur at low frequency, more precise treatment strategies and additional combinational approaches are required.
Authors: Anna Buder; Ellen Heitzer; Julie Waldispühl-Geigl; Sabrina Weber; Tina Moser; Maximilian J Hochmair; Klaus Hackner; Peter Errhalt; Ulrike Setinek; Martin Filipits Journal: Biomolecules Date: 2021-04-21
Authors: Zofia Piotrowska; Hideko Isozaki; Jochen K Lennerz; Justin F Gainor; Inga T Lennes; Viola W Zhu; Nicolas Marcoux; Mandeep K Banwait; Subba R Digumarthy; Wenjia Su; Satoshi Yoda; Amanda K Riley; Varuna Nangia; Jessica J Lin; Rebecca J Nagy; Richard B Lanman; Dora Dias-Santagata; Mari Mino-Kenudson; A John Iafrate; Rebecca S Heist; Alice T Shaw; Erica K Evans; Corinne Clifford; Sai-Hong I Ou; Beni Wolf; Aaron N Hata; Lecia V Sequist Journal: Cancer Discov Date: 2018-09-26 Impact factor: 39.397