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Sci Rep. 2019 Jan 24;9(1):648. doi: 10.1038/s41598-018-37059-8.

A Ras destabilizer KYA1797K overcomes the resistance of EGFR tyrosine kinase inhibitor in KRAS-mutated non-small cell lung cancer.

Park J1,2, Cho YH1,2, Shin WJ1,2, Lee SK1,2, Lee J1,2, Kim T1,2, Cha PH1,2, Yang JS1,2, Cho J3, Min DS1,4, Han G1,2, Lee HY3, Choi KY5,6.

Author information

1
Translational Research Center for Protein Function Control, Yonsei University, Seoul, Korea.
2
Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
3
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea.
4
Department of Molecular Biology, College of Natural Science, Pusan National University, Pusan, Korea.
5
Translational Research Center for Protein Function Control, Yonsei University, Seoul, Korea. kychoi@yonsei.ac.kr.
6
Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea. kychoi@yonsei.ac.kr.

Abstract

The epidermal growth factor receptor (EGFR) inhibitors such as erlotinib and gefitinib are widely used for treatment of non-small cell lung cancer (NSCLC), but they have shown limited efficacy in an unselected population of patients. The KRAS mutations, which are identified in approximately 20% of NSCLC patients, have shown to be associated with the resistance to the EGFR tyrosine kinase inhibitors (TKIs). Currently, there is no clinically available targeted therapy which can effectively inhibit NSCLC tumors harboring KRAS mutations. This study aims to show the effectiveness of KYA1797K, a small molecule which revealed anti-cancer effect in colorectal cancer by destabilizing Ras via inhibiting the Wnt/β-catenin pathway, for the treatment of KRAS-mutated NSCLC. While erlotinib fail to have anti-transforming effect in NSCLC cell lines harboring KRAS mutations, KYA1797K effectively inhibited the Ras-ERK pathway in KRAS-mutant NSCLC cell lines. As a result, KYA1797K treatment suppressed the growth and transformation of KRAS mutant NSCLC cells and also induced apoptosis. Furthermore, KYA1797K effectively inhibited Kras-driven tumorigenesis in the KrasLA2 mouse model by suppressing the Ras-ERK pathway. The destabilization of Ras via inhibition of the Wnt/β-catenin pathway is a potential therapeutic strategy for KRAS-mutated NSCLC that is resistant to EGFR TKI.

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