Overview

• Researchers at DKFZ and Stanford used somatic CRISPR/Cas9 to engineer mouse models that precisely recapitulate the common EML4-ALK V1 and V3 fusion breakpoints.
• Mice harboring the V3 fusion developed larger tumors faster and had shorter survival than V1 models, indicating greater intrinsic oncogenicity for V3.
• Pharmacologic testing showed V1-driven tumor cells were highly sensitive to the ALK inhibitor lorlatinib, whereas V3-driven cells exhibited resistance.
• Systematic inactivation of 29 tumor suppressor genes revealed variant-specific effects on tumor growth and treatment response, with alterations such as PTEN loss modifying drug sensitivity.
• Analysis of the largest available EML4-ALK patient dataset found distinct co-mutation patterns by variant, supporting movement toward more granular diagnostics and future variant-stratified trials.