Identifying the Intergenic ALK Fusion LOC388942‐ALK as a Driver of Non–Small Cell Lung Cancer
ABSTRACT ALK fusions, such as the classic EML4‐ALK, are known drivers of lung cancer and effective therapeutic targets. However, variant ALK fusions, including intergenic fusions like LOC388942‐ALK (LA), have been detected in increasing numbers of patients, with their roles in tumorigenesis and ALK...
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| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-04-01
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| Series: | MedComm |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/mco2.70154 |
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| Summary: | ABSTRACT ALK fusions, such as the classic EML4‐ALK, are known drivers of lung cancer and effective therapeutic targets. However, variant ALK fusions, including intergenic fusions like LOC388942‐ALK (LA), have been detected in increasing numbers of patients, with their roles in tumorigenesis and ALK inhibitor resistance remaining unclear. Using CRISPR/Cas9, we generated the LA fusion in A549 and H441 cells, confirming elevated ALK expression via qRT‐PCR and immunohistochemistry (IHC) staining. Functional analyses showed that LA significantly promoted tumor growth in vitro and in vivo while conferring increased resistance to alectinib. RNA‐seq revealed upregulation of the FOS pathway in LA tumors, identifying FOS as a potential therapeutic target. Subsequently, we demonstrated that FOS disruption and inhibition sensitized LA tumors to treatment. RNA‐seq profiling demonstrated that FOS depletion in LOC388942‐ALK tumor significantly downregulated multiple oncogenic pathways related to cell cycle progression, DNA replication fidelity, and extracellular matrix remodeling, suggesting a pivotal role of FOS in maintaining tumor growth. These findings establish LOC388942‐ALK as a novel oncogenic driver in lung cancer, highlighting its role in tumor growth and ALK inhibitor resistance. Targeting FOS may provide a promising therapeutic strategy for tumors harboring this intergenic fusion. |
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| ISSN: | 2688-2663 |