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.© 2025 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.