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

Christoph Heining(German Cancer Research Center), Peter Horak(Heidelberg University), Sebastian Uhrig(Heidelberg University), Paula Codó(German Cancer Research Center), Barbara Klink(German Cancer Research Center), Barbara Hutter(Heidelberg University), Martina Fröhlich(Heidelberg University), David Bonekamp(Heidelberg University), Daniela Richter(German Cancer Research Center), Katja Steiger(Institut für Rundfunktechnik), Roland Penzel(Heidelberg University), Volker Endris(Heidelberg University), Karl Roland Ehrenberg(National Center for Tumor Diseases), Stephanie De Frank(National Center for Tumor Diseases), Kortine Kleinheinz(Heidelberg University), Umut H. Toprak(Heidelberg University), Matthias Schlesner(Heidelberg University), Ranadip Mandal(Heidelberg University), L.S. Schulz(Garmisch-Partenkirchen Medical Center), Helmut Lambertz(Garmisch-Partenkirchen Medical Center), Sebastian Fetscher(University of Lübeck), Michael Bitzer(University Children's Hospital Tübingen), Nisar P. Malek(University Children's Hospital Tübingen), Marius Horger(University Children's Hospital Tübingen), Nathalia A. Giese(Heidelberg University), Oliver Strobel(Heidelberg University), Thilo Hackert(Heidelberg University), Christoph Springfeld(National Center for Tumor Diseases), Lars Feuerbach(Heidelberg University), Frank Bergmann(Heidelberg University), Evelin Schröck(German Cancer Research Center), Christof von Kalle(Heidelberg University), Wilko Weichert(Institut für Rundfunktechnik), Claudia Scholl(Heidelberg University), Claudia R. Ball(German Cancer Research Center), Albrecht Stenzinger(Heidelberg University), Benedikt Brors(Heidelberg University), Stefan Fröhling(Heidelberg University), Hanno Glimm(German Cancer Research Center)
Cancer Discovery
May 25, 2018
10.1158/2159-8290.cd-18-0036
Cited by 239Open Access
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Abstract

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. Cancer Discov; 8(9); 1087–95. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 1047

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