배성진 (고신대학교)

한빛사논문

조회324

배성진Sung-Jin Bae

고신대학교

CV File 110 kb

Exp. Mol. Med., May 01 2024, | https://doi.org/10.1038/s12276-024-01221-2 Targeting pyruvate dehydrogenase kinase 1 overcomes EGFR C797S mutation-driven osimertinib resistance in non-small cell lung cancer

Wonyoung Park^1,2, Shibo Wei³, Chu-Long Xie^4,5, Jung Ho Han⁶, Bo-Sung Kim^1,2, Bosung Kim^1,2, Jung-Sook Jin², Eun-Sun Yang², Min Kyoung Cho⁷, Dongryeol Ryu⁸, Hao-Xian Yang^4,5, Sung-Jin Bae⁷ and Ki-Tae Ha^1,2

¹Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, Gyeongsangnam-do 50612, Republic of Korea.

²Korean Medical Research Center for Healthy Aging, Pusan National University, Yangsan, Gyeongsangnam-do 50612, Republic of Korea.

³Department of Precision Medicine, School of Medicine, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi-do 16419, Republic of Korea.

⁴Department of Thoracic Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China.

⁵State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China.

⁶Korean Medicine Application Center, Korea Institute of Oriental Medicine, Daegu 41062, Republic of Korea.

⁷Department of Molecular Biology and Immunology, Kosin University College of Medicine, Busan 49267, Republic of Korea.

⁸Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea.

Corresponding authors : Sung-Jin Bae or Ki-Tae Ha.

Abstract

Osimertinib, a selective third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), effectively targets the EGFR T790M mutant in non-small cell lung cancer (NSCLC). However, the newly identified EGFR C797S mutation confers resistance to osimertinib. In this study, we explored the role of pyruvate dehydrogenase kinase 1 (PDK1) in osimertinib resistance. Patients exhibiting osimertinib resistance initially displayed elevated PDK1 expression. Osimertinib-resistant cell lines with the EGFR C797S mutation were established using A549, NCI-H292, PC-9, and NCI-H1975 NSCLC cells for both in vitro and in vivo investigations. These EGFR C797S mutant cells exhibited heightened phosphorylation of EGFR, leading to the activation of downstream oncogenic pathways. The EGFR C797S mutation appeared to increase PDK1-driven glycolysis through the EGFR/AKT/HIF-1α axis. Combining osimertinib with the PDK1 inhibitor leelamine helped successfully overcome osimertinib resistance in allograft models. CRISPR-mediated PDK1 knockout effectively inhibited tumor formation in xenograft models. Our study established a clear link between the EGFR C797S mutation and elevated PDK1 expression, opening new avenues for the discovery of targeted therapies and improving our understanding of the roles of EGFR mutations in cancer progression.

논문정보

형식Research article
게재일2024년 05월 (BRIC 등록일 2024-05-03)
연구진국내 연구진
분야 의약학 > 종양의학

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