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- Title
A small-molecule compound D6 overcomes EGFR-T790M-mediated resistance in non-small cell lung cancer.
- Authors
Tang, Xiaolong; Cheng, Lizhi; Li, Guo; Yan, Yong-Ming; Su, Fengting; Huang, Dan-Ling; Zhang, Shuping; Liu, Zuojun; Qian, Minxian; Li, Ji; Cheng, Yong-Xian; Liu, Baohua
- Abstract
Non-small cell lung cancer (NSCLC) is a deadly and highly prevalent malignancy. Targeting activated-EGFR mutations in NSCLC via EGFR tyrosine kinase inhibitor (EGFR-TKI) initially achieves a profound therapeutic response, but resistance frequently evolves, reducing treatment options. Here, we present a small-molecule compound D6 which selectively inhibits tumor cell growth and migration in NSCLC cells with EGFR-TKI-resistant T790M-EGFR-activated mutations (T790M-EGFR-AM), e.g., L858R/T790M, 19Del/T790M and L858R/T790M/C797S. D6 mimics a natural product isolated from the roots of Codonopsis pilosula and selectively competes with T790M-EGFR-AM to bind to HSP90, thus facilitating the ubiquitination dependent proteasomal degradation of T790M-EGFR-AM. By contrast, D6 has little impact on typical HSP90 chaperone activity, suggesting low systemic toxicity. Promisingly, D6 combined with erlotinib or osimertinib shows efficacy in overcoming the EGFR-TKIs-resistance in NSCLCs. Our study raises an alternative strategy to overcome T790M-mediated EGFR-TKI resistance in NSCLC via targeting the protein–protein interaction of HSP90 and T790M-EGFR by intervention with D6. Tang et al. propose the use of a small molecule compound D6 to treat EGFRTKI resistant tumors. The authors demonstrate potent and selective inhibition of NSCLC with T790M-mediated EGFR-TKI resistance through inhibiting HSP90-mediated protein–protein interaction.
- Subjects
NON-small-cell lung carcinoma; PROTEIN-tyrosine kinase inhibitors; HEAT shock proteins; SMALL molecules; PROTEIN-protein interactions
- Publication
Communications Biology, 2021, Vol 4, Issue 1, p1
- ISSN
2399-3642
- Publication type
Article
- DOI
10.1038/s42003-021-02906-4