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  3. A small-molecule compound D6 overcomes EGFR-T790M-mediated resistance in non-small cell lung cancer

A small-molecule compound D6 overcomes EGFR-T790M-mediated resistance in non-small cell lung cancer

  • Commun Biol. 2021 Dec 13;4(1):1391. doi: 10.1038/s42003-021-02906-4.
Xiaolong Tang  # 1,  Lizhi Cheng  # 2,  Guo Li  # 3,  Yong-Ming Yan 2,  Fengting Su 2,  Dan-Ling Huang 2,  Shuping Zhang 3,  Zuojun Liu 2,  Minxian Qian 2,  Ji Li 3,  Yong-Xian Cheng 4,  Baohua Liu 5 6 7 8
Affiliations

Affiliations

  • 1 Shenzhen Key Laboratory for Systemic Aging and Intervention (SKL-SAI), School of Basic Medical Sciences; Institute for Inheritance-Based Innovation of Chinese Medicine, School of Pharmaceutical Sciences, Shenzhen University, Shenzhen, China. tangxiaolong05@126.com.
  • 2 Shenzhen Key Laboratory for Systemic Aging and Intervention (SKL-SAI), School of Basic Medical Sciences; Institute for Inheritance-Based Innovation of Chinese Medicine, School of Pharmaceutical Sciences, Shenzhen University, Shenzhen, China.
  • 3 Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.
  • 4 Shenzhen Key Laboratory for Systemic Aging and Intervention (SKL-SAI), School of Basic Medical Sciences; Institute for Inheritance-Based Innovation of Chinese Medicine, School of Pharmaceutical Sciences, Shenzhen University, Shenzhen, China. yxcheng@szu.edu.cn.
  • 5 Shenzhen Key Laboratory for Systemic Aging and Intervention (SKL-SAI), School of Basic Medical Sciences; Institute for Inheritance-Based Innovation of Chinese Medicine, School of Pharmaceutical Sciences, Shenzhen University, Shenzhen, China. ppliew@szu.edu.cn.
  • 6 Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Shenzhen University, Shenzhen, China. ppliew@szu.edu.cn.
  • 7 National Engineering Research Center for Biotechnology (Shenzhen); Marshall Laboratory of Biomedical Engineering; International Cancer Center, Shenzhen University, Shenzhen, China. ppliew@szu.edu.cn.
  • 8 Shenzhen Bay Laboratory, Shenzhen, China. ppliew@szu.edu.cn.
  • # Contributed equally.
PMID: 34903832 DOI: 10.1038/s42003-021-02906-4
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.

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