한빛사 논문
Jiyeon Yun1,*, Min Hee Hong1,2,*, Seok-Young Kim1, Chae-Won Park1, Soyoung Kim1, Mi Ran Yun1,3, Han Na Kang1,3, Kyoung-Ho Pyo1, Sung Sook Lee 4, Jong Sung Koh5, Ho-Juhn Song5, Dong Kyun Kim6, Young-Sung Lee6, Se-Woong Oh6, Soongyu Choi6, Hye Ryun Kim1,2,#, and Byoung Chul Cho1,2,3,#
1 Yonsei Cancer Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea.
2 Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
3 JE-UK Institute for Cancer Research, JEUK Co. Ltd., Gumi-City, Kyungbuk, Republic of Korea.
4 Department of Hematology-Oncology Inje University Haeundae Paik Hospital, Busan, Korea,
5Genosco Inc., Cambridge, MA.
6Yuhan R&D Institute, Yuhan Corporation, Seoul, Korea
* These authors contributed equally to this work and should be considered co-first authors
# These authors contributed equally to this work and should be considered co-corresponding authors
Corresponding Author: Byoung Chul Cho, Yonsei Cancer Center, Division of Medical Oncology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Korea. Yonsei Cancer Center, Division of Medical Oncology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Korea; Hye Ryun Kim, M.D., Ph.D. Yonsei Cancer Center, Division of Medical Oncology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Korea.
Abstract
Purpose:Given that osimertinib is the only approved third-generation EGFR-TKI against EGFR activating and resistant T790M mutated NSCLC, additional mutant-selective inhibitors with a higher efficacy, especially for brain metastases, with favorable toxicity profile are still needed. In this study, we investigated the antitumor efficacy of YH25448, an oral, mutant-selective, irreversible third-generation EGFR-TKI in preclinical models. Experimental Design:Antitumor activity of YH25448 was investigated in vitro using mutant EGFR-expressing Ba/F3 cells and various lung cancer cell lines. In vivo antitumor efficacy, ability to penetrate the blood-brain barrier (BBB), and skin toxicity of YH25448 were examined and compared with those of osimertinib using cell lines- and PDX model. Results:Compared to osimertinib, YH25448 showed a higher selectivity and potency in kinase assay and mutant EGFR-expressing Ba/F3 cells. In various cell line models harboring EGFR activating and T790M mutation, YH25448 effectively inhibited EGFR downstream signaling pathways, leading to cellular apoptosis. When compared in vivo at equimolar concentrations, YH25448 produced significantly better tumor regression than osimertinib. Importantly, YH25448 induced profound tumor regression in brain metastasis model with excellent brain/plasma and tumor/brain area under the concentration-time curve value. YH25448 rarely suppressed the levels of p-EGFR in hair follicles, leading to less keratosis than osimertinib in animal model. The potent systemic and intracranial activity of YH25448 has been shown in an ongoing phase I/II clinical trial for advanced EGFR T790M mutated NSCLC (NCT03046992). Conclusions:Our findings suggest that YH25448 is a promising third-generation EGFR inhibitor, which may be more effective and better tolerated than the currently approved osimertinib.
Keywords: YH25448, EGFR-mutant lung cancer, Brain metastasis, Tyrosine-kinase inhibitor
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