YH25448, an irreversible EGFR-TKI with potent intracranial activity in EGFR mutant non-small cell lung cancer

Jiyeon Yun, Min Hee Hong, Seok Young Kim, Chae Won Park, Soyoung Kim, Mi Ran Yun, Han Na Kang, Kyoung Ho Pyo, Sung Sook Lee, Jong Sung Koh, Ho Juhn Song, Dong Kyun Kim, Young Sung Lee, Se Woong Oh, Soongyu Choi, Hye Ryun Kim, Byoung Chul Cho

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Purpose: Given that osimertinib is the only approved thirdgeneration EGFR-TKI against EGFR activating and resistant T790M mutated non-small cell lung cancer (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 with 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.

Original languageEnglish
Pages (from-to)2575-2587
Number of pages13
JournalClinical Cancer Research
Volume25
Issue number8
DOIs
Publication statusPublished - 2019 Apr 15

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Non-Small Cell Lung Carcinoma
Cell Line
Brain
Neoplasm Metastasis
Keratosis
Phase II Clinical Trials
Clinical Trials, Phase I
Hair Follicle
Blood-Brain Barrier
Brain Neoplasms
osimertinib
Lung Neoplasms
Neoplasms
Research Design
Phosphotransferases
Animal Models
Apoptosis
Skin
Mutation

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Yun, Jiyeon ; Hong, Min Hee ; Kim, Seok Young ; Park, Chae Won ; Kim, Soyoung ; Yun, Mi Ran ; Kang, Han Na ; Pyo, Kyoung Ho ; Lee, Sung Sook ; Koh, Jong Sung ; Song, Ho Juhn ; Kim, Dong Kyun ; Lee, Young Sung ; Oh, Se Woong ; Choi, Soongyu ; Kim, Hye Ryun ; Cho, Byoung Chul. / YH25448, an irreversible EGFR-TKI with potent intracranial activity in EGFR mutant non-small cell lung cancer. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 8. pp. 2575-2587.
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title = "YH25448, an irreversible EGFR-TKI with potent intracranial activity in EGFR mutant non-small cell lung cancer",
abstract = "Purpose: Given that osimertinib is the only approved thirdgeneration EGFR-TKI against EGFR activating and resistant T790M mutated non-small cell lung cancer (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 with 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.",
author = "Jiyeon Yun and Hong, {Min Hee} and Kim, {Seok Young} and Park, {Chae Won} and Soyoung Kim and Yun, {Mi Ran} and Kang, {Han Na} and Pyo, {Kyoung Ho} and Lee, {Sung Sook} and Koh, {Jong Sung} and Song, {Ho Juhn} and Kim, {Dong Kyun} and Lee, {Young Sung} and Oh, {Se Woong} and Soongyu Choi and Kim, {Hye Ryun} and Cho, {Byoung Chul}",
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Yun, J, Hong, MH, Kim, SY, Park, CW, Kim, S, Yun, MR, Kang, HN, Pyo, KH, Lee, SS, Koh, JS, Song, HJ, Kim, DK, Lee, YS, Oh, SW, Choi, S, Kim, HR & Cho, BC 2019, 'YH25448, an irreversible EGFR-TKI with potent intracranial activity in EGFR mutant non-small cell lung cancer', Clinical Cancer Research, vol. 25, no. 8, pp. 2575-2587. https://doi.org/10.1158/1078-0432.CCR-18-2906

YH25448, an irreversible EGFR-TKI with potent intracranial activity in EGFR mutant non-small cell lung cancer. / Yun, Jiyeon; Hong, Min Hee; Kim, Seok Young; Park, Chae Won; Kim, Soyoung; Yun, Mi Ran; Kang, Han Na; Pyo, Kyoung Ho; Lee, Sung Sook; Koh, Jong Sung; Song, Ho Juhn; Kim, Dong Kyun; Lee, Young Sung; Oh, Se Woong; Choi, Soongyu; Kim, Hye Ryun; Cho, Byoung Chul.

In: Clinical Cancer Research, Vol. 25, No. 8, 15.04.2019, p. 2575-2587.

Research output: Contribution to journalArticle

TY - JOUR

T1 - YH25448, an irreversible EGFR-TKI with potent intracranial activity in EGFR mutant non-small cell lung cancer

AU - Yun, Jiyeon

AU - Hong, Min Hee

AU - Kim, Seok Young

AU - Park, Chae Won

AU - Kim, Soyoung

AU - Yun, Mi Ran

AU - Kang, Han Na

AU - Pyo, Kyoung Ho

AU - Lee, Sung Sook

AU - Koh, Jong Sung

AU - Song, Ho Juhn

AU - Kim, Dong Kyun

AU - Lee, Young Sung

AU - Oh, Se Woong

AU - Choi, Soongyu

AU - Kim, Hye Ryun

AU - Cho, Byoung Chul

PY - 2019/4/15

Y1 - 2019/4/15

N2 - Purpose: Given that osimertinib is the only approved thirdgeneration EGFR-TKI against EGFR activating and resistant T790M mutated non-small cell lung cancer (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 with 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.

AB - Purpose: Given that osimertinib is the only approved thirdgeneration EGFR-TKI against EGFR activating and resistant T790M mutated non-small cell lung cancer (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 with 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.

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