EML4-ALK variant-specific genetic interactions shape lung tumorigenesis

Oncogenic fusions of EML4 and ALK occur in ~5% of lung adenocarcinomas. EML4-ALK variants have distinct breakpoints within EML4, but the functional differences among these variants remain poorly understood. Here we use CRISPR/Cas9 somatic genome editing to generate autochthonous mouse models of the two most common EML4-ALK variants 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 in vivo we show that many tumor suppressor genes have dramatically variant-specific effects on tumorigenesis. Pharmacogenomic analyses suggest that tumor genotype can also modify responses to therapy. Analysis of a large human EML4-ALK lung cancer cohort identified differences in the genomic landscape depending on the EML4-ALK variant. These findings demonstrate functional heterogeneity between EML4-ALK variants, suggesting that EML4-ALK variants behave more like distinct oncogenes than a uniform entity. More broadly, these findings highlight the dramatic impact of oncogenic fusions partner proteins and coincident tumor suppressor gene alterations on the biology of oncogenic fusion driven cancer. Overall design: RNA-Seq profiling of sorted EGFP positive neoplastic cells from EML4-ALK V1 and V3-driven tumors that were either Setd2-proficient (sgNeo) or Setd2-deficient (sgSetd2).