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  3. Targeting both wild-type EGFR and its drug-resistant mutants with erlotinib-aptamer conjugates

Targeting both wild-type EGFR and its drug-resistant mutants with erlotinib-aptamer conjugates

  • Eur J Med Chem. 2025 Oct 15:296:117871. doi: 10.1016/j.ejmech.2025.117871.
Yan Li 1,  Jian Song 1,  Ruixin Ge 1,  Xiangrui Luo 1,  Ping Zhou 1,  Hanyue Lei 2,  Rouhan Qian 2,  Fan Zhang 1,  Wei Pan 1,  Miao Chen 3,  Jingrui Li 3,  Xifeng Dong 4,  Tianliang Li 1,  Sijin Wu 2,  Jun Zhou 5,  Songbo Xie 6
Affiliations

Affiliations

  • 1 Center for Cell Structure and Function, Collaborative Innovation Center of Cell Biology in Universities of Shandong, College of Life Sciences, Shandong Normal University, Jinan, 250014, China.
  • 2 Wisdom Lake Academy of Pharmacy, Xi'an Jiaotong-Liverpool University, Suzhou, 215028, China.
  • 3 School of Life Sciences and Medicine, Shandong University of Technology, Zibo, 255500, China.
  • 4 Department of Hematology, Tianjin Key Laboratory of Bone Marrow Failure and Malignant Hemopoietic Clone Control, Tianjin Institute of Hematology, Tianjin Medical University General Hospital, Tianjin, 300052, China.
  • 5 Center for Cell Structure and Function, Collaborative Innovation Center of Cell Biology in Universities of Shandong, College of Life Sciences, Shandong Normal University, Jinan, 250014, China; State Key Laboratory of Medicinal Chemical Biology, Haihe Laboratory of Cell Ecosystem, College of Life Sciences, Nankai University, Tianjin, 300071, China. Electronic address: junzhou@sdnu.edu.cn.
  • 6 The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Medical University, Ministry of Education International Joint Laboratory of Ocular Diseases, Tianjin Key Laboratory of Ocular Trauma, Tianjin Institute of Eye Health and Eye Diseases, China-UK "Belt and Road" Ophthalmology Joint Laboratory, Department of Ophthalmology, Tianjin Medical University General Hospital, Tianjin, 300052, China. Electronic address: songboxie@tmu.edu.cn.
PMID: 40554308 DOI: 10.1016/j.ejmech.2025.117871
Abstract

The epidermal growth factor receptor (EGFR) mutation is an actionable oncogenic driver in non-small-cell lung Cancer (NSCLC). Although multiple generations of EGFR-tyrosine kinase inhibitors (EGFR-TKIs) have been approved for the treatment of advanced NSCLC, acquired drug resistance after long-term administration challenges their therapeutic efficacy. In this study, using the first-generation agent erlotinib as a warhead for EGFR and an aptamer targeting insulin-like growth factor 2 receptor (IGF2R) as a recruiter for the lysosome-shuttling receptor, we develop a pan-EGFR lysosome-targeting chimera (LYTAC). A series of EGFR degraders with different linker lengths are generated, among which LY-dE#5 is the most effective degrader that directs EGFR to the lysosomal pathway for degradation. Importantly, LY-dE#5 drives not only the downregulation of the wild-type but also the mutants which include 19del, L858R/T790M, 19del/T790M/C797S, and L858R/T790M/C797S, exhibiting superior antitumor activity over Osimertinib. Further in vitro and in vivo studies demonstrate that LY-dE#5 effectively suppresses the growth of EGFR-driven Cancer cells. These data indicate that the erlotinib-aptamer conjugate is an efficient pan-EGFR degrader that holds the translational potential for Cancer treatment to overcome the common drug-resistance issues of EGFR-TKIs.

Keywords

Aptamer; Drug resistance; Epidermal growth factor receptor; Lysosome-targeting chimera; Targeted protein degradation.

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