An ErbB2 splice variant lacking exon 16 drives lung carcinoma

Significance Lung cancers are frequently driven by well-characterized mutations in proto-oncogenes, including ERBB2. Evidence from other cancers demonstrates that ERBB2 is also activated by alternative splicing that causes skipping of exon 16. Here, we find evidence for increased ERBB2 alternative splicing in a subset of lung cancers and a range of other solid tumors, including deletions and previously undescribed mutations promoting exon 16 skipping. We show that the ERBB2 isoform lacking exon 16 transforms lung epithelial cells in vitro and in vivo, arguing that alternative splicing of ERBB2 is a mechanism promoting lung carcinogenesis. These findings extend our knowledge of lung cancer biology and may lead to improved patient stratification to facilitate future use of ERBB2-targeted therapies. Lung cancer causes more deaths annually than any other malignancy. A subset of non-small cell lung cancer (NSCLC) is driven by amplification and overexpression or activating mutation of the receptor tyrosine kinase (RTK) ERBB2. In some contexts, notably breast cancer, alternative splicing of ERBB2 causes skipping of exon 16, leading to the expression of an oncogenic ERBB2 isoform (ERBB2ΔEx16) that forms constitutively active homodimers. However, the broader implications of ERBB2 alternative splicing in human cancers have not been explored. Here, we have used genomic and transcriptomic analysis to identify elevated ERBB2ΔEx16 expression in a subset of NSCLC cases, as well as splicing site mutations facilitating exon 16 skipping and deletions of exon 16 in a subset of these lung tumors and in a number of other carcinomas. Supporting the potential of ERBB2ΔEx16 as a lung cancer driver, its expression transformed immortalized lung epithelial cells while a transgenic model featuring inducible ERBB2ΔEx16 specifically in the lung epithelium rapidly developed lung adenocarcinomas following transgene induction. Collectively, these observations indicate that ERBB2ΔEx16 is a lung cancer oncogene with potential clinical importance for a proportion of patients.