@article{7fb274ee32ad4ef4b474763ee4f035b9,
title = "NRG1 fusions in KRAS 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 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.",
author = "Christoph Heining and Peter Horak and Sebastian Uhrig and Codo, {Paula L.} and Barbara Klink and Barbara Hutter and Martina Fr{\"o}hlich and David Bonekamp and Daniela Richter and Katja Steiger and Roland Penzel and Volker Endris and Ehrenberg, {Karl Roland} and Stephanie Frank and Kortine Kleinheinz and Toprak, {Umut H.} and Matthias Schlesner and Ranadip Mandal and Lothar Schulz and Helmut Lambertz and Sebastian Fetscher and Michael Bitzer and Malek, {Nisar P.} and Marius Horger and Giese, {Nathalia A.} and Oliver Strobel and Thilo Hackert and Christoph Springfeld and Lars Feuerbach and Frank Bergmann and Evelin Schr{\"o}ck and {von Kalle}, Christof and Wilko Weichert and Claudia Scholl and Ball, {Claudia R.} and Albrecht Stenzinger and Benedikt Brors and Stefan Fr{\"o}hling and Hanno Glimm",
note = "Funding Information: D. Bonekamp has received honoraria from the speakers{\textquoteright} bureau of Profound Medical Inc. W. Weichert reports receiving a commercial research grant from Roche, has received honoraria from the speakers bureaus of Pfizer, Roche, MSD, BMS, AstraZeneca, and Novartis, and is a consultant/advisory board member for Pfizer, Roche, MSD, BMS, AstraZeneca, and Novartis. A. Stenzinger is a consultant/advisory board member for AstraZeneca, BMS, Novartis, and Roche. No potential conflicts of interest were disclosed by the other authors. Funding Information: The authors thank the DKFZ-HIPO Sample Processing Laboratory, the DKFZ Genomics and Proteomics Core Facility, and the DKFZ-HIPO Data Management Group for technical support. We also thank K. Beck, K. Willmund, R. Eils, and P. Lichter for infrastructure and program development within DKFZ-HIPO. Tissue samples were provided by the NCT and Pancobank/EPZ-Surgery Heidelberg Tissue Banks in accordance with Biomaterialbank Heidelberg regulations and after approval by the Ethics Committee of Heidelberg University. This work was supported by grant 021 from DKFZ-HIPO, the NCT 3.0 Precision Oncology Program (NCT POP), NCT 3.0 Section Personalized Medicine (NCT3.0_2015.4 TransOnco), and a grant from the NCT 3.0 Integrative Projects in Basic Cancer Research Program. P.L. Codo and S. Frank were supported by a postdoctoral fellowship and a Heinrich F.C. Behr stipend from the DKFZ, respectively. PancoBank/ EPZ-Surgery was supported by BMBF grants 01ZX1305C/1605C, EU ERA-Net TRANSCAN01KT1506, and Heidelberger Stiftung Chirurgie. Funding Information: The authors thank the DKFZ-HIPO Sample Processing Laboratory, the DKFZ Genomics and Proteomics Core Facility, and the DKFZ-HIPO Data Management Group for technical support. We also thank K. Beck, K. Willmund, R. Eils, and P. Lichter for infrastructure and program development within DKFZ-HIPO. Tissue samples were provided by the NCT and Pancobank/EPZ-Surgery Heidelberg Tissue Banks in accordance with Biomaterialbank Heidelberg regulations and after approval by the Ethics Committee of Heidelberg University. This work was supported by grant 021 from DKFZ-HIPO, the NCT 3.0 Precision Oncology Program (NCT POP), NCT 3.0 Section Personalized Medicine (NCT3.0_2015.4 TransOnco), and a grant from the NCT 3.0 Integrative Projects in Basic Cancer Research Program. P.L. Codo and S. Frank were supported by a postdoctoral fellowship and a Heinrich F.C. Behr stipend from the DKFZ, respectively. PancoBank/ EPZ-Surgery was supported by BMBF grants 01ZX1305C/1605C, EU ERA-Net TRANSCAN01KT1506, and Heidelberger Stiftung Chirurgie. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Publisher Copyright: {\textcopyright}2018 American Association for Cancer Research.",
year = "2018",
month = sep,
doi = "10.1158/2159-8290.CD-18-0036",
language = "English",
volume = "8",
pages = "1087--1095",
journal = "Cancer Discovery",
issn = "2159-8274",
publisher = "American Association for Cancer Research Inc.",
number = "9",
}