ArticleGenome biology2026
A comprehensive functional atlas of ALK kinase domain variants reveals resistance landscape to ALK inhibitors.
Article in Genome biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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Who cites it
2 citing papers in PubMed.
- Three decades of anaplastic lymphoma kinase: from physiological roles to cancer and immune evasion.Cancer metastasis reviews · 2026Review
- A comprehensive functional atlas of ALK kinase domain variants reveals resistance landscape to ALK inhibitors.Genome biology · 2026Article
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4 authors.
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Abstract
backgroundALK gene fusions are key oncogenic drivers in cancers such as non-small cell lung cancer, where they define a molecular subtype responsive to ALK tyrosine kinase inhibitors (TKIs). However, resistance commonly arises due to single nucleotide variants (SNVs) within the ALK tyrosine kinase domain, many of which remain variants of uncertain significance (VUSs).
resultsTo systematically profile resistance, we use prime editing to generate and assess 3,208 ALK variants covering 99% of all possible SNVs across exons 20-28, along with intronic variants. We evaluate drug resistance across three generations of ALK TKIs: alectinib, lorlatinib, and zotizalkib. These high-resolution resistance landscapes validate known resistance mutations (e.g., G1202R, L1196M), identify previously uncharacterized resistance-associated VUSs, and reveal distinct patterns of drug-specific and shared resistance across inhibitors. Structural mapping further contextualizes resistance-associated variants relative to the ATP-binding pocket and distal regions associated with resistance.
conclusionsThis study provides a comprehensive functional atlas of ALK tyrosine kinase domain variants under TKI selection, offering a valuable experimental framework for interpreting resistance-associated variants. Although derived from in vitro models and therefore context dependent, this resource complements existing clinical and genomic knowledge and may aid in the functional interpretation of ALK variants observed in ALK-driven cancers.
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