Abstract 5171: The EGFR-PROTAC molecule TY-2719 attenuates acquired resistance to 3rd-generation EGFR TKIs and augments the efficacy of KRAS mutant inhibitors in solid tumors

Abstract Introduction: Acquired resistance to EGFR-TKIs poses a significant challenge in the clinical management of non-small-cell lung cancer (NSCLC). TY-2719, an effective oral, broad-spectrum EGFR-PROTAC developed by TYK Medicines, was designed to overcome the resistance associated with third-generation EGFR-TKIs. TY-2719 not only demonstrated an excellent safety profile but also enhanced the efficacy of KRAS mutant inhibitors in NSCLC and pancreatic ductal adenocarcinoma (PDAC) models. Results: TY-2719 effectively degraded EGFR with the L858R mutation in NSCLC H3255 cells and the L858R/T790M/C797S and 19del/C797S mutations in BaF3 cells. However, it did not degrade EGFR in cells expressing wild-type EGFR, such as A549 and H358 cells. It demonstrated excellent antiproliferative activity against EGFR mutants but did not inhibit the growth of normal cells, including NHEK, MCF-10A, IOSE-80, and FHC cells. TY-2719 overcame osimertinib resistance in BaF3 L858R/C797S and BaF3 del19/C797S CDX mouse models and enhanced the efficacy of Divarasib (GDC-6036) and pan-KRASi Daroxonrasib (RMC-6236) in NSCLC H1972 and H2122 cells, as well as Daroxonrasib in MiaPaca 2 (PDAC, KRAS G12D), AsPC-1, SU.86.86, PANC-1 (PDAC, KRAS G12D), and Capan-1 (PDAC KRAS G12V). Common side effects of EGFR-TKIs, including osimertinib, are skin reactions and diarrhea due to wild-type EGFR inhibition in normal tissues. The DMPK characteristics of TY-2719 were excellent, with superior toxicity profiles in Sprague-Dawley rat experiments. The body weights of male and female rats showed no difference between the 100 mg/kg (mpk) TY-2719 treated group and the vehicle group after three weeks of treatment. No diarrhea was observed in rats treated with 100 mg/kg TY-2719, either. In the BN Norway female rat rash experiment, after 28 days, all rats in the 37.5 mpk gefitinib control group showed obvious rash symptoms, whereas in the TY-2719 100 mpk group, all rats' skin appeared normal. Meanwhile, treatment with 100 mpk TY-2719 had no significant effect on the body weight of Norway rats compared to that of the vehicle group. Taken together, we have identified a potent and safe EGFR-PROTAC molecule which may grant new therapeutic opportunities to overcome drug resistance of 3rd -generation EGFR TKIs in NSCLC patients and enhance the efficacy of KRAS mutant inhibitors in NSCLC and PDAC. Citation Format: Apeng Liang, Hongqiang Li, Zhiyong He, Zhengfei Guo, Meihua Li, Shunxun Han, Guangbin Liu, Xi Wang, Yanyan Liu, Ling Fang, Yi Long, Xiang Zhang, Wei Wu, Chengshan Niu, Jun Li, Yusheng Wu. The EGFR-PROTAC molecule TY-2719 attenuates acquired resistance to 3rd-generation EGFR TKIs and augments the efficacy of KRAS mutant inhibitors in solid tumors 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 5171.