2024 World Conference on Lung Cancer (WCLC) - ePosters-EP.02B.02 The Functional Roles of Intergenic ALK Fusions in NSCLC

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The research by Xiaoqian Zhai from West China Hospital, Sichuan University, investigates the role of intergenic ALK fusions in non-small cell lung cancer (NSCLC). ALK fusions, such as EML4-ALK, are known drivers and therapeutic targets in NSCLC. However, about 15% involve variant intergenic fusions, whose biological roles and response to ALK inhibitors are not well-understood. The study focuses on a newly identified intergenic fusion, LOC388942-ALK (LA), which appeared in a patient who initially responded to the ALK inhibitor crizotinib but quickly relapsed.<br /><br />To explore LA's role in NSCLC, the researchers used CRISPR-Cas gene editing to create the LA fusion in NSCLC cell lines and primary lung organoids, which were then transplanted into mice. The team assessed tumor growth, protein levels, and resistance to ALK inhibitors through in vitro and in vivo models. Transcriptomics analysis via RNA-seq evaluated the molecular mechanisms involved.<br /><br />Results demonstrated that LA fusions increase ALK protein levels and promote rapid tumor growth, both in vitro and in vivo. Mice with LA fusions developed tumors that were more aggressive compared to controls and resistant to ALK inhibitors. The fusion led to a significant upregulation in the EMT (epithelial-mesenchymal transition) and TNF (tumor necrosis factor) pathways, suggesting these as potential mechanisms behind tumor progression.<br /><br />The study concludes that the LA fusion acts as a driver of NSCLC but shows resistance to existing ALK inhibitors, indicating a need for specific diagnostic inclusion of LA variants and the development of targeted treatments for affected patients. The research highlights LA's potential role in tumorigenesis through pathways involving significant genes like FOS, pushing for further exploration and better therapeutic strategies in treating NSCLC with intergenic ALK fusions.

Asset Subtitle

Xiaoqian Zhai

Meta Tag

Speaker Xiaoqian Zhai

Topic Tumor Biology – Preclinical Biology

Keywords

non-small cell lung cancer

NSCLC

ALK fusions

intergenic fusions

LOC388942-ALK

CRISPR-Cas gene editing

tumor growth

ALK inhibitors

epithelial-mesenchymal transition

tumorigenesis