Ltk, also known as leukocyte tyrosine kinase, is a receptor tyrosine kinase. It is an ER-resident receptor that regulates secretion by controlling the number of ER exit sites and ER-to-Golgi transport [4]. It also plays a role in the regulation of neuronal polarity and cortical migration by inhibiting IGF1R activity [2].

In non-small-cell lung cancer (NSCLC), the CLIP1-LTK fusion has been identified as an oncogenic driver. The kinase activity of the CLIP1-LTK fusion protein is constitutively activated and has transformation potential. Lorlatinib, an ALK inhibitor, can inhibit its kinase activity, suppress proliferation and induce apoptosis in Ba/F3 cells expressing CLIP1-LTK. However, LTK mutations, such as the L650F mutation, can lead to resistance to lorlatinib, and gilteritinib may overcome this resistance [1,3]. In Sjogren's syndrome, LTK deficiency induces macrophage M2 polarization and ameliorates the disease by reducing chemokine CXCL13 [5].

In conclusion, Ltk has diverse functions in different biological processes and disease conditions. In NSCLC, the CLIP1-LTK fusion is a targetable oncogenic driver, and understanding LTK-related resistance mechanisms is crucial for treatment. In Sjogren's syndrome, LTK is involved in macrophage polarization and disease progression, highlighting its potential as a therapeutic target in these disease areas.