LTK fusions: A new target emerges in non-small cell lung cancer

Abstract

Identification of targetable fusions as oncogenic drivers in non-small cell lung cancer has transformed its diagnostic and therapeutic paradigm. In a recent article in Nature, Izumi et al. report the discovery of CLIP1-LTK fusion as a novel oncogenic driver in lung cancer, targetable using the ALK tyrosine kinase inhibitor lorlatinib.

Figure 1.. Schematic of LTK signaling and homology model.

(A) The wild-type LTK receptor (right; red box indicates the kinase domain) promotes signaling through the RAS/MAPK and PI3K-AKT pathways upon activation. The CLIP1-LTK fusion (left; adapted from Izumi et al., Nature 2021) results in constitutive activation of LTK (indicated by star) and activation of AKT and ERK. In the fusion protein schematic, green represents cytoskeleton-associated protein glycine-rich (CAP-Gly) domain; blue represents coiled-coil domain (CC). Note: Schematic is not drawn to scale. (B) LTK homology model (colored pink) built from lorlatinib co-crystal structure (colored green) in the ALK kinase domain. LTK and ALK share 95% homology in residues within 6 Å of lorlatinib, which is the most critical for binding. The single difference within this distance corresponds to ALK A1200 and LTK S594. LTK residues mapped onto the ALK structure were energy minimized using the OPLS3 forcefield with the remainder of the protein fixed. Known clinical ALK resistance mutations (against various generations of ALK inhibitors and involved as part of compound mutations against lorlatinib) are colored orange with corresponding ALK (blue text) and LTK (black text) residues shown.