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

Jieun Park, Yong Hee Cho, Wook Jin Shin, Sang Kyu Lee, Jae Heon Lee, Taehyung Kim, Pu Hyeon Cha, Jee Sun Yang, Jaebeom Cho, Do Sik Min, Gyoonhee Han, Ho Young Lee, Kang-Yell Choi

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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.

Original languageEnglish
Article number648
JournalScientific reports
Volume9
Issue number1
DOIs
Publication statusPublished - 2019 Dec 1

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Epidermal Growth Factor Receptor
Non-Small Cell Lung Carcinoma
Protein-Tyrosine Kinases
Catenins
Wnt Signaling Pathway
MAP Kinase Signaling System
Mutation
Therapeutics
Cell Line
Colorectal Neoplasms
Neoplasms
Carcinogenesis
Apoptosis
Growth
Population

All Science Journal Classification (ASJC) codes

  • General

Cite this

Park, Jieun ; Cho, Yong Hee ; Shin, Wook Jin ; Lee, Sang Kyu ; Lee, Jae Heon ; Kim, Taehyung ; Cha, Pu Hyeon ; Yang, Jee Sun ; Cho, Jaebeom ; Min, Do Sik ; Han, Gyoonhee ; Lee, Ho Young ; Choi, Kang-Yell. / A Ras destabilizer KYA1797K overcomes the resistance of EGFR tyrosine kinase inhibitor in KRAS-mutated non-small cell lung cancer. In: Scientific reports. 2019 ; Vol. 9, No. 1.
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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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A Ras destabilizer KYA1797K overcomes the resistance of EGFR tyrosine kinase inhibitor in KRAS-mutated non-small cell lung cancer. / Park, Jieun; Cho, Yong Hee; Shin, Wook Jin; Lee, Sang Kyu; Lee, Jae Heon; Kim, Taehyung; Cha, Pu Hyeon; Yang, Jee Sun; Cho, Jaebeom; Min, Do Sik; Han, Gyoonhee; Lee, Ho Young; Choi, Kang-Yell.

In: Scientific reports, Vol. 9, No. 1, 648, 01.12.2019.

Research output: Contribution to journalArticle

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AU - Park, Jieun

AU - Cho, Yong Hee

AU - Shin, Wook Jin

AU - Lee, Sang Kyu

AU - Lee, Jae Heon

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AU - Cha, Pu Hyeon

AU - Yang, Jee Sun

AU - Cho, Jaebeom

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AU - Han, Gyoonhee

AU - Lee, Ho Young

AU - Choi, Kang-Yell

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