2024 World Conference on Lung Cancer (WCLC) - ePosters-EP.12F.02 Brigatinib, a Newly Discovered AXL Inhibitor, and Suppresses AXL Mediated Acquired Resistance to Osimertinib in NSCLC

EP.12F.02 Brigatinib, a Newly Discovered AXL Inhibitor, and Suppresses AXL Mediated Acquired Resistance to Osimertinib in NSCLC

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The study conducted by Conghua Lu and colleagues at the Daping Hospital, Army Medical University, focuses on overcoming acquired resistance to osimertinib, a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), in non-small cell lung cancer (NSCLC) caused by the receptor tyrosine-protein kinase AXL. AXL is frequently expressed in EGFR-mutated NSCLC and contributes significantly to the acquired resistance to EGFR-TKIs such as osimertinib.<br /><br />The researchers aimed to explore new anti-AXL treatments capable of tackling this resistance both in vitro and in vivo. Through the use of various models, including cell viability assays, colonial survival studies, and xenograft models, they identified and tested approximately 510 small molecule compounds to find inhibitors with antiproliferative effects against AXL. Their screenings revealed brigatinib, a second-generation ALK inhibitor, as an effective AXL inhibitor.<br /><br />The study demonstrated that brigatinib, in combination with osimertinib, effectively counteracted resistance. The combined treatment worked through mechanisms such as antagonizing K48-linked ubiquitin-dependent AXL degradation and inhibiting AXL signaling. This combination significantly sensitized NSCLC cells with high AXL expression that were resistant to osimertinib, enhancing the anti-tumor effects in resistant NSCLC cell xenografts.<br /><br />The findings suggest that targeting AXL using brigatinib might present a promising therapeutic approach for overcoming osimertinib resistance in NSCLC patients, providing a potential improvement in the treatment landscape for those with EGFR-mutated lung cancers facing drug resistance.

Asset Subtitle

Conghua Lu

Meta Tag

Speaker Conghua Lu

Topic Metastatic Non-small Cell Lung Cancer – Targeted Therapy

Keywords

osimertinib resistance

AXL inhibitor

non-small cell lung cancer

EGFR-TKI

brigatinib

antiproliferative effects

ALK inhibitor

NSCLC xenografts

AXL signaling

EGFR-mutated lung cancer