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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   LA2   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.

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