Ltk, also known as leukocyte tyrosine kinase, is an ER-resident receptor tyrosine kinase [5]. It plays a role in regulating secretion, as depletion or inhibition of LTK reduces the number of ER exit sites and slows ER-to-Golgi transport, and it interacts with and phosphorylates Sec12 [5]. LTK is also involved in neuronal polarity and cortical migration, where it, along with ALK, inhibits IGF1R activity. Loss of LTK and/or Alk in mouse models causes a multiple axon phenotype, delays neuronal migration, and disrupts cortical patterning [2].

In non-small-cell lung cancer (NSCLC), a novel CLIP1-LTK fusion has been identified as an oncogenic driver [1,4,6]. This fusion is present in 0.4% of NSCLCs and is mutually exclusive with other known oncogenic drivers [1]. The kinase activity of the CLIP1-LTK fusion protein is constitutively activated and has transformation potential [1]. Lorlatinib, an ALK inhibitor, can inhibit CLIP1-LTK kinase activity, suppress proliferation, and induce apoptosis in Ba/F3 cells expressing CLIP1-LTK, and a patient with NSCLC harbouring the fusion showed a good response to lorlatinib treatment [1]. However, acquired resistance may develop, especially through LTK mutations. For example, the L650F mutation in LTK shows high resistance to lorlatinib, but gilteritinib can overcome this resistance [3]. In Sjogren's syndrome, LTK deficiency induces macrophage M2 polarization and ameliorates the disease by reducing chemokine CXCL13 [7].

In summary, LTK has diverse functions in biological processes. In the context of disease, its role in NSCLC as part of the CLIP1-LTK fusion and in Sjogren's syndrome through regulation of macrophage polarization has been revealed. Mouse models have been crucial in understanding its functions in neuronal development, and research on LTK in cancer and autoimmune diseases provides potential therapeutic targets.