ALK ATI in solid tumours: biological evidence, diagnostic challenges, and clinical relevance. a narrative review

Anaplastic lymphoma kinase (ALK) can be activated in cancer through gene fusions, activating mutations, copy-number alterations, and abnormal transcription. ALK ATI is a truncated ALK transcript initiated from an alternative promoter within intron 19. It retains the intracellular kinase domain but lacks the extracellular and transmembrane regions of full-length ALK. The biological and clinical implications of this transcript remain unsettled. The discovery study reported ALK phosphorylation, oncogenic signalling, tumour formation, and crizotinib sensitivity in experimental models. Subsequent work described nuclear chromatin effects and cancer stem-cell phenotypes in selected models. However, independent experiments did not consistently reproduce growth-factor-independent transformation or sensitivity to ALK inhibitors, and melanoma models expressing ALK ATI generally showed low phosphorylation and no selective drug response. Clinical studies are retrospective, use heterogeneous assays, and report inconsistent prevalence and prognostic associations across melanoma, sarcoma, ovarian carcinoma, and histiocytic neoplasms. Importantly, ALK immunohistochemistry and break-apart fluorescence in situ hybridization cannot establish ALK ATI: confirmation requires an RNA-based assay designed to demonstrate transcription from intron 19 into ALK exons 20-29, together with exclusion of a canonical ALK fusion. Current evidence therefore supports ALK ATI as a context-dependent biological phenomenon rather than a validated tumour-agnostic driver or predictive biomarker. ALK-inhibitor treatment should not be selected solely on the basis of ALK ATI outside a clinical trial or a carefully documented individual assessment.