NRG1 fusions in KRAS wild-type pancreatic cancer

Christoph Heining, Peter Horak, Sebastian Uhrig, Paula L. Codo, Barbara Klink, Barbara Hutter, Martina Fröhlich, David Bonekamp, Daniela Richter, Katja Steiger, Roland Penzel, Volker Endris, Karl Roland Ehrenberg, Stephanie Frank, Kortine Kleinheinz, Umut H. Toprak, Matthias Schlesner, Ranadip Mandal, Lothar Schulz, Helmut LambertzSebastian Fetscher, Michael Bitzer, Nisar P. Malek, Marius Horger, Nathalia A. Giese, Oliver Strobel, Thilo Hackert, Christoph Springfeld, Lars Feuerbach, Frank Bergmann, Evelin Schröck, Christof von Kalle, Wilko Weichert, Claudia Scholl, Claudia R. Ball, Albrecht Stenzinger, Benedikt Brors, Stefan Fröhling, Hanno Glimm*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

111 Citations (Scopus)

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 KRAS wild-type (KRASWT) tumors (4 of 17). These alterations included recurrent NRG1 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 NRG1-rearranged tumors that had proved resistant to standard treatment. Our findings demonstrate that systematic screening of KRASWT tumors for oncogenic fusion genes will substantially improve the therapeutic prospects for a sizeable fraction of patients with PDAC. SIGNIFICANCE: Advanced PDAC is a malignancy with few treatment options that lacks molecular mechanism-based therapies. Our study uncovers recurrent gene rearrangements such as NRG1 fusions as disease-driving events in KRASWT tumors, thereby providing novel insights into oncogenic signaling and new therapeutic options in this entity.

Original languageEnglish
Pages (from-to)1087-1095
Number of pages9
JournalCancer Discovery
Volume8
Issue number9
DOIs
Publication statusPublished - Sep 2018
Externally publishedYes

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