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

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 N...

Full description

Saved in:
Bibliographic Details
Published in:Scientific reports 2019-01, Vol.9 (1), p.648-648, Article 648
Main Authors: Park, Jieun, Cho, Yong-Hee, Shin, Wook-Jin, Lee, Sang-Kyu, Lee, JaeHeon, Kim, Taehyung, Cha, Pu-Hyeon, Yang, Jee Sun, Cho, Jaebeom, Min, Do Sik, Han, Gyoonhee, Lee, Ho-Young, Choi, Kang-Yell
Format: Article
Language:English
Subjects:
Apoptosis
Colorectal carcinoma
Enzyme inhibitors
Epidermal growth factor
Epidermal growth factor receptors
Extracellular signal-regulated kinase
Gefitinib
K-Ras protein
Lung cancer
Metabolic pathways
Mutants
Mutation
Non-small cell lung carcinoma
Small cell lung carcinoma
Tumorigenesis
Tyrosine kinase inhibitors
Wnt protein
β-Catenin
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 Kras 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.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-018-37059-8