2023 World Conference on Lung Cancer (Posters)-P2.09. Inhibition of AXL and Mcl-1 Contributes to Eradicating Tolerance to EGFR-TKI Lazertinib in Lung Cancer Cells Expressing Mutant EGFR

P2.09. Inhibition of AXL and Mcl-1 Contributes to Eradicating Tolerance to EGFR-TKI Lazertinib in Lung Cancer Cells Expressing Mutant EGFR - PDF(Abstract)

Back to course

Pdf Summary

In patients with advanced non-small cell lung cancer (NSCLC) expressing mutant EGFR, treatment with EGFR-tyrosine kinase inhibitors (TKIs) is the current standard of care. Lazertinib, a novel third-generation EGFR-TKI, has shown promising results in extending progression-free survival in patients with EGFR-activating mutations. However, many patients eventually develop resistance to Lazertinib. In this study, the researchers aimed to investigate the mechanisms underlying Lazertinib tolerance and identify potential therapeutic targets.<br /><br />The researchers evaluated the protein expression and drug sensitivity in NSCLC cells expressing mutant EGFR when treated with Lazertinib or other drugs. They found that Lazertinib initially inhibited cell proliferation but after a certain period of time, cell expansion was observed. Further investigation revealed that the expression of AXL, a protein associated with drug resistance, was enhanced after exposure to Lazertinib. Knocking down AXL reduced tumor viability more than any other factor. Combining Lazertinib with an AXL inhibitor suppressed cell viability compared to Lazertinib alone, indicating that AXL activation contributes to Lazertinib tolerance. However, long-term exposure to Lazertinib and an AXL inhibitor led to cell proliferation again. The researchers also observed increased expression of the anti-apoptotic protein MCL-1 in response to Lazertinib plus AXL inhibitor treatment. Triple therapy with Lazertinib, AXL inhibitor, and MCL-1 inhibitor inhibited cell growth.<br /><br />Overall, the study suggests that AXL and MCL-1 signaling play pivotal roles in Lazertinib resistance in NSCLC cells expressing mutant EGFR. Targeting these mechanisms genetically or pharmacologically enhanced and prolonged tumor growth inhibition. The findings highlight the need for further research to translate these findings into clinical practice.

Asset Subtitle

Yohei Matsui

Meta Tag

Speaker Yohei Matsui

Topic Metastatic NSCLC: Targeted Therapy - EGFR/HER2

Keywords

advanced non-small cell lung cancer

NSCLC

mutant EGFR

EGFR-tyrosine kinase inhibitors

Lazertinib

progression-free survival

drug resistance

AXL

MCL-1

therapeutic targets