The CLIP1–LTK Fusion Is an Oncogenic Driver of NSCLC

Although targeted therapy against known oncogenic drivers has improved outcomes for patients with non–small cell lung cancer (NSCLC), those with unknown oncogenic drivers lack therapeutic options. To address this, Izumi, Matsumoto, and colleagues applied whole-transcriptome sequencing of NSCLC samples with no known oncogenic drivers obtained from the lung cancer genome screening platform LC-SCRUM-Asia. In-frame fusion transcripts of the microtubule plus-end-tracking protein CLIP1 and the receptor tyrosine kinase LTK were uncovered. Notably, all three patients with NSCLC that harbored the CLIP1–LTK fusion were negative for other known oncogenic drivers, suggesting that these drivers are mutually exclusive. As multiple coiled coil domains were predicted to be present in CLIP1 upstream of the LTK domain, it was hypothesized that these domains allowed protein dimerization and constitutive activation of LTK kinase. Mouse embryonic fibroblasts transfected with the CLIP1–LTK fusion were found to have more robust phosphorylation of LTK than cells transfected with wild-type LTK. Additionally, cells transfected with the CLIP1–LTK fusion exhibited larger colonies than cells with wild-type LTK or EGFR overexpression in vitro, demonstrating that CLIP1–LTK has transforming activity. Furthermore, only mouse xenografts with cells transduced with the CLIP1–LTK fusion formed tumors, whereas mice injected with cells overexpressing LTK did not. Lorlatinib, an inhibitor originally for ALK tyrosine kinases, was also effective in blocking LTK phosphorylation, inhibiting CLIP1–LTK-induced cell viability and growth, as well as inhibiting tumor growth of CLIP1–LTK cell injected into mice. The patient positive for the CLIP1–LTK fusion also received lorlatinib as an LTK-targeted therapy, and the 2- and 5-month follow-up CT images showed rapid and significant reduction of both primary and metastic tumors. Overall, this study highlights the CLIP1–LTK fusion as a novel oncogenic driver of NSCLC and demonstrates lorlatinib as a potential therapy for patients with NSCLC who harbor this fusion.

Izumi H, Matsumoto S, Liu J, Tanaka K, Mori S, Hayashi K, et al. The CLIP1-LTK fusion is an oncogenic driver in non-small-cell lung cancer. Nature 2021;600:319–23.

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