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CC BY 4.0 · Pharmaceutical Fronts 2024; 06(04): e323-e335
DOI: 10.1055/s-0044-1791541
Review Article

Advances in Small-Molecule C-KIT/PDGFRα Inhibitors for the Treatment of Gastrointestinal Stromal Tumors

Xuan Zheng   #
1   State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, School of Pharmacy, Jinan University, Guangzhou, People's Republic of China
,
Hong Liang   #
1   State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, School of Pharmacy, Jinan University, Guangzhou, People's Republic of China
,
Yang Zhou
1   State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, School of Pharmacy, Jinan University, Guangzhou, People's Republic of China
,
Xiaoyun Lu
1   State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, School of Pharmacy, Jinan University, Guangzhou, People's Republic of China
› Author Affiliations Funding This work was financially supported by the National Natural Science Foundation of China (Grant Nos. 82273763 and 82103968), the International Cooperation Project of Guangdong Science and Technology Program (Grant No. 2022A0505050045), Guangdong Basic and Applied Basic Research Foundation (Grant No. 2022B515130008), the Open Project of State Key Laboratory of Respiratory Disease (Grant No. SKLRD-OP-202313), and Wang Kuancheng Young Scholar of Jinan University and the High-Performance Public Computing Service Platform of Jinan University.
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Abstract

Stem cell factor receptor (C-KIT) or platelet-derived growth factor receptor α (PDGFRα) gene mutations have been identified as oncogenic drivers for most gastrointestinal stromal tumors (GISTs). Thus, small-molecule inhibitors of C-KIT or PDGFRα have emerged as effective treatments for GISTs. Although the currently approved first- to fourth-line drugs are initially effective against GISTs, the inevitable development of drug resistance remains an unmet challenge. To address secondary mutations leading to drug resistance, several novel selective C-KIT/PDGFRα small-molecule inhibitors have been developed and clinically studied. This review summarizes the pathogenesis, treatment, and drug resistance mechanisms of GISTs and briefly describes current challenges and future efforts for GIST treatment using small-molecule kinase inhibitors.

Keywords

PDGFRα - C-KIT - GISTs - kinase inhibitors - clinical resistance

# These authors contributed equally to this work.




Publication History

Received: 28 October 2023

Accepted: 06 September 2024

Article published online:
17 October 2024

© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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