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| Home > Publications database > EML4-ALK variant-specific genetic interactions shape lung tumorigenesis. |
| Journal Article | DKFZ-2025-01954 |
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2025
[Verlag nicht ermittelbar]
Philadelphia, Pa.
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Please use a persistent id in citations: doi:10.1158/2159-8290.CD-24-1417
Abstract: Diverse fusions of EML4 and ALK are oncogenic drivers in lung adenocarcinomas. EML4-ALK variants have distinct breakpoints within EML4, but their functional differences remain poorly understood. Here, we use somatic genome editing to generate autochthonous mouse models of EML4-ALK-driven lung tumors and show that V3 is more oncogenic than V1. By employing multiplexed genome editing and quantifying the effects of 29 putative tumor suppressor genes on V1- and V3-driven lung cancer growth, we show that many tumor suppressor genes have variant-specific effects on tumorigenesis. Pharmacogenomic analyses further suggest that tumor genotype can influence therapeutic responses. Analysis of human EML4-ALK-positive lung cancers also identified variant-specific differences in their genomic landscapes. These findings suggest that EML4-ALK variants behave more like distinct oncogenes rather than a uniform entity and highlight the dramatic impact of oncogenic fusion partner proteins and coincident tumor suppressor gene alterations on the biology of oncogenic fusion-driven cancers.
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