Abstract Background: Although three generations of EGFR tyrosine kinase inhibitors (TKIs) have achieved remarkable clinical success, resistance driven by secondary EGFR mutations remains a major therapeutic challenge in non-small cell lung cancer (NSCLC). To address this unmet need, we developed HJ-004, a potent, selective, and orally bioavailable pan-EGFR mutation degrader that targets classical, rare, and exon 20 insertion mutations. Methods and Results: HJ-004 induces potent and selective degradation of mutant EGFR proteins, but not wild-type EGFR, in Ba/F3 and human cell lines harboring diverse EGFR alterations, with DC50 values below 5 nM, and exhibits strong antiproliferative activity. Mechanistic studies confirmed E3 ligase-mediated ubiquitination and proteasomal degradation. In vivo, HJ-004 produces dose-dependent tumor regression in both murine and human-derived cell-derived xenograft (CDX) and patient-derived xenograft (PDX) models carrying various resistant EGFR genotypes. Pharmacokinetic evaluation demonstrated favorable PK properties, including 30-40% oral bioavailability across multiple species and sustained exposure supporting once-daily dosing. Importantly, HJ-004 exhibits an approximately 10-fold therapeutic window in both mice and monkeys, without any notable skin rashes or diarrhea, indicating excellent selectivity and safety margin. Conclusions: HJ-004 represents a first-in-class pan-EGFR mutation targeted protein degrader that effectively overcomes osimertinib resistance across classical, rare, and exon 20 insertion variants. Its potent degradation activity, broad antitumor efficacy, and favorable pharmacokinetic and safety profiles support advancement into clinical development as a next-generation therapy for EGFR-mutated NSCLC. HJ-004 was independently developed by Jing Medicine Technology (Shanghai) Ltd., and has received IND clearance from both the U.S. FDA and China NMPA. Citation Format: Li Zeng, Yao Liu, Ya Geng, Yue Zhu. HJ-004, a potent and selective pan-EGFR mutation targeted protein degrader (TPD) that effectively overcomes osimertinib resistance in EGFR-mutant NSCLC abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5161.
Zeng et al. (Fri,) studied this question.