NRG1 Fusions in KRAS Wild-Type Pancreatic Cancer

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 pharmac...

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Published in:Cancer discovery 2018-09, Vol.8 (9), p.1087-1095
Main Authors: Heining, Christoph, Horak, Peter, Uhrig, Sebastian, Codo, Paula L, Klink, Barbara, Hutter, Barbara, Fröhlich, Martina, Bonekamp, David, Richter, Daniela, Steiger, Katja, Penzel, Roland, Endris, Volker, Ehrenberg, Karl Roland, Frank, Stephanie, Kleinheinz, Kortine, Toprak, Umut H, Schlesner, Matthias, Mandal, Ranadip, Schulz, Lothar, Lambertz, Helmut, Fetscher, Sebastian, Bitzer, Michael, Malek, Nisar P, Horger, Marius, Giese, Nathalia A, Strobel, Oliver, Hackert, Thilo, Springfeld, Christoph, Feuerbach, Lars, Bergmann, Frank, Schröck, Evelin, von Kalle, Christof, Weichert, Wilko, Scholl, Claudia, Ball, Claudia R, Stenzinger, Albrecht, Brors, Benedikt, Fröhling, Stefan, Glimm, Hanno
Format: Article
Language:English
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Summary: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 wild-type ( ) tumors (4 of 17). These alterations included recurrent 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 -rearranged tumors that had proved resistant to standard treatment. Our findings demonstrate that systematic screening of tumors for oncogenic fusion genes will substantially improve the therapeutic prospects for a sizeable fraction of patients with PDAC. Advanced PDAC is a malignancy with few treatment options that lacks molecular mechanism-based therapies. Our study uncovers recurrent gene rearrangements such as fusions as disease-driving events in tumors, thereby providing novel insights into oncogenic signaling and new therapeutic options in this entity. .
ISSN:2159-8274
2159-8290
DOI:10.1158/2159-8290.cd-18-0036