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)ERBB2. In some contexts, notably breast cancer, alternative splicing ofERBB2causes skipping of exon 16, leading to the expression of an oncogenic ERBB2 isoform (ERBB2ΔEx16) that forms constitutively active homodimers. However, the broader implications ofERBB2alternative splicing in human cancers have not been explored. Here, we have used genomic and transcriptomic analysis to identify elevatedERBB2ΔEx16expression 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 thatERBB2ΔEx16is a lung cancer oncogene with potential clinical importance for a proportion of patients.