2024 World Conference on Lung Cancer (WCLC) - ePosters-EP.03F.02 Exploration of Acquired Resistance Mechanisms to the 4th-Generation EGFR-TKI in EGFR-Mutated Lung Cancer

EP.03F.02 Exploration of Acquired Resistance Mechanisms to the 4th-Generation EGFR-TKI in EGFR-Mutated Lung Cancer - An in Vitro Study

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The study led by Shota Fukuda investigates the potential utility of a fourth-generation EGFR tyrosine kinase inhibitor (EGFR-TKI), BI4020, and explores mechanisms of resistance using various lung cancer cell lines. Lung cancer patients with activating EGFR mutations often develop resistance to earlier generations of EGFR-TKIs due to mutations such as T790M and C797S. Fourth-generation EGFR-TKIs, like BI4020, are being developed to overcome these resistances.<br /><br />In the study, four lung cancer cell lines (HCC827, HCC4006, H1975, and PC9), all of which harbor EGFR mutations, were exposed to increasing concentrations of BI4020. Acquired resistant cell lines were established and examined for secondary EGFR kinase domain mutations, discovering none. Instead, resistance mechanisms varied across cell lines. <br /><br />For HCC827, BI4020 resistance was linked with MET gene amplification, which was reversible with the administration of MET-TKI capmatinib, aligning with previous findings where resistance is a result of MET amplification. In HCC4006 and H1975, epithelial-mesenchymal transition (EMT) characterized by changes in protein expression and cell morphology, was observed as a mechanism of resistance.<br /><br />In PC9, BI4020 resistance was marked by increased MET phosphorylation without MET gene amplification. However, sensitivity was not restored with capmatinib, suggesting that MET expression does not necessarily correlate with resistance. Additionally, increased FGFR1 expression in PC9 was identified but not resolved by the FGFR1 inhibitor Ponatinib.<br /><br />In a separate analysis involving 195 non-small cell lung cancer (NSCLC) patients with EGFR mutations, TP53 was identified as the most common co-existing mutation, mutually exclusive from MDM2 mutations.<br /><br />The study underscores the diverse resistance mechanisms lung cancer cells develop against EGFR-TKIs, indicating that resistance pathways are complex and often involve off-target changes rather than secondary EGFR mutations.

Asset Subtitle

Shota Fukuda

Meta Tag

Speaker Shota Fukuda

Topic Tumor Biology – Translational Biology

Keywords

EGFR-TKI

BI4020

lung cancer

resistance mechanisms

EGFR mutations

MET amplification

epithelial-mesenchymal transition

TP53 mutation

non-small cell lung cancer

fourth-generation inhibitors