<i>NRG1</i> Fusions in <i>KRAS</i> Wild-Type Pancreatic Cancer

Abstract

We used whole-genome and transcriptome sequencing to identify clinically actionable genomic alterations in young adults with pancreatic ductal adenocarcinoma (PDAC). Molecular characterization of 17 patients with PDAC enrolled in a precision oncology program revealed gene fusions amenable to pharmacologic inhibition by small-molecule tyrosine kinase inhibitors in all patients with <i>KRAS</i> wild-type (<i>KRAS</i>^WT) tumors (4 of 17). These alterations included recurrent <i>NRG1</i> rearrangements predicted to drive PDAC development through aberrant ERBB receptor-mediated signaling, and pharmacologic ERBB inhibition resulted in clinical improvement and remission of liver metastases in 2 patients with <i>NRG1</i>-rearranged tumors that had proved resistant to standard treatment. Our findings demonstrate that systematic screening of <i>KRAS</i>^WT tumors for oncogenic fusion genes will substantially improve the therapeutic prospects for a sizeable fraction of patients with PDAC.<b>Significance:</b> Advanced PDAC is a malignancy with few treatment options that lacks molecular mechanism-based therapies. Our study uncovers recurrent gene rearrangements such as <i>NRG1</i> fusions as disease-driving events in <i>KRAS</i>^wt tumors, thereby providing novel insights into oncogenic signaling and new therapeutic options in this entity. <i>Cancer Discov; 8(9); 1087-95. ©2018 AACR.</i><i>This article is highlighted in the In This Issue feature, p. 1047</i>.