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(Slides)

Back to course

Pdf Summary

This study investigated the mechanisms of tolerance to the EGFR-TKI Lazertinib in lung cancer cells expressing mutant EGFR. Lazertinib is a third-generation EGFR-TKI that targets the EGFR kinase domain. While it has been shown to extend progression-free survival in patients receiving monotherapy, many eventually develop resistance to the drug. The researchers aimed to identify potential therapeutic targets to address this issue.<br /><br />The study found that Lazertinib inhibited the growth of multiple EGFR-mutated NSCLC cell lines. Screening using siRNAs revealed that knockdown of the AXL gene enhanced the growth suppression effect of Lazertinib in PC-9 cells. In long-term exposure experiments, combination therapy with an AXL inhibitor enhanced cell growth inhibition, but eradication of the cells was not achieved. Western blot assays showed that the combination treatment increased the expression of the antiapoptotic protein MCL-1.<br /><br />Further experiments showed that triple therapy targeting EGFR, AXL, and MCL-1 enhanced cell growth inhibition in PC-9 and HCC4011 cells. Knockdown of MCL-1 increased the expression of Cleaved-caspase3, an apoptosis-related protein, in PC-9 cells. The evaluation of triple therapy also showed an increase in cell apoptosis when an MCL-1 inhibitor was added to the combination of Lazertinib and the AXL inhibitor.<br /><br />In conclusion, the study identified AXL and MCL-1 as potential factors contributing to drug tolerance to Lazertinib in EGFR-mutated NSCLC cells. These findings suggest that AXL and MCL-1 play pivotal roles in intrinsic resistance to Lazertinib and overcoming adaptive resistance to the drug. Targeting these proteins in combination with Lazertinib may provide a more effective therapeutic strategy for lung cancer patients.

Asset Subtitle

Yohei Matsui

Meta Tag

Speaker Yohei Matsui

Topic Metastatic NSCLC: Targeted Therapy - EGFR/HER2

Keywords

EGFR-TKI

Lazertinib

lung cancer

mutant EGFR

tolerance mechanisms

third-generation EGFR-TKI

therapeutic targets

AXL gene

MCL-1

triple therapy