An ErbB2 splice variant lacking exon 16 drives lung carcinoma.

Abstract

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) <i>ERBB2</i> In some contexts, notably breast cancer, alternative splicing of <i>ERBB2</i> 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 <i>ERBB2</i> alternative splicing in human cancers have not been explored. Here, we have used genomic and transcriptomic analysis to identify elevated <i>ERBB2ΔEx16</i> 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 <i>ERBB2ΔEx16</i> is a lung cancer oncogene with potential clinical importance for a proportion of patients.