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Research Briefs

Response to ERBB3-Directed Targeted Therapy in NRG1-Rearranged Cancers

Alexander Drilon, Romel Somwar, Biju P. Mangatt, Henrik Edgren, Patrice Desmeules, Anja Ruusulehto, Roger S. Smith, Lukas Delasos, Morana Vojnic, Andrew J. Plodkowski, Joshua Sabari, Kenneth Ng, Joseph Montecalvo, Jason Chang, Huichun Tai, William W. Lockwood, Victor Martinez, Gregory J. Riely, Charles M. Rudin, Mark G. Kris, Maria E. Arcila, Christopher Matheny, Ryma Benayed, Natasha Rekhtman, Marc Ladanyi and Gopinath Ganji
Alexander Drilon
Memorial Sloan Kettering Cancer Center
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  • For correspondence: drilona@mskcc.org
Romel Somwar
Memorial Sloan Kettering Cancer Center
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Biju P. Mangatt
GlaxoSmithKline
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Henrik Edgren
MediSapiens
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Patrice Desmeules
Memorial Sloan Kettering Cancer Center
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Anja Ruusulehto
-, MediSapiens
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Roger S. Smith
Memorial Sloan Kettering Cancer Center
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Lukas Delasos
Memorial Sloan Kettering Cancer Center
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Morana Vojnic
Memorial Sloan Kettering Cancer Center
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Andrew J. Plodkowski
Memorial Sloan Kettering Cancer Center
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  • ORCID record for Andrew J. Plodkowski
Joshua Sabari
Memorial Sloan Kettering Cancer Center
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Kenneth Ng
Memorial Sloan Kettering Cancer Center
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Joseph Montecalvo
Pathology, Memorial Sloan Kettering Cancer Center
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Jason Chang
Memorial Sloan Kettering Cancer Center
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Huichun Tai
Memorial Sloan Kettering Cancer Center
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William W. Lockwood
University of British Columbia
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Victor Martinez
University of British Columbia
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Gregory J. Riely
Memorial Sloan Kettering Cancer Center
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Charles M. Rudin
Memorial Sloan Kettering Cancer Center
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Mark G. Kris
Memorial Sloan Kettering Cancer Center
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Maria E. Arcila
Memorial Sloan Kettering Cancer Center
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Christopher Matheny
GlaxoSmithKline
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Ryma Benayed
Memorial Sloan Kettering Cancer Center
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Natasha Rekhtman
Memorial Sloan Kettering Cancer Center
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Marc Ladanyi
Memorial Sloan Kettering Cancer Center
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Gopinath Ganji
GlaxoSmithKline
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DOI: 10.1158/2159-8290.CD-17-1004
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Abstract

NRG1 rearrangements are oncogenic drivers that are enriched in invasive mucinous adenocarcinomas (IMAs) of the lung. The oncoprotein binds ERBB3-ERBB2 heterodimers and activates downstream signaling, supporting a therapeutic paradigm of ERBB3/ERBB2 inhibition. As proof of concept, a durable response was achieved with anti-ERBB3 monoclonal antibody therapy (GSK2849330) in an exceptional responder with an NRG1-rearranged IMA on a phase 1 trial (NCT01966445). In contrast, response was not achieved with anti-ERBB2 therapy (afatinib) in four NRG1-rearranged IMA patients (including the index patient post-GSK2849330). While in vitro data supported the use of either ERBB3 or ERBB2 inhibition, these clinical results were consistent with more profound anti-tumor activity and downstream signaling inhibition with anti-ERBB3 versus anti-ERBB2 therapy in an NRG1-rearranged patient-derived xenograft model. Analysis of 8,984 and 17,485 tumors in The Cancer Genome Atlas and MSK-IMPACT datasets, respectively, identified NRG1 rearrangements with novel fusion partners in multiple histologies, including breast, head and neck, renal, lung, ovarian, pancreatic, prostate, and endometrial cancers.

  • Received September 7, 2017.
  • Revision received March 7, 2018.
  • Accepted March 28, 2018.
  • Copyright ©2018, American Association for Cancer Research.
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Published OnlineFirst April 2, 2018
doi: 10.1158/2159-8290.CD-17-1004

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Response to ERBB3-Directed Targeted Therapy in NRG1-Rearranged Cancers
Alexander Drilon, Romel Somwar, Biju P. Mangatt, Henrik Edgren, Patrice Desmeules, Anja Ruusulehto, Roger S. Smith, Lukas Delasos, Morana Vojnic, Andrew J. Plodkowski, Joshua Sabari, Kenneth Ng, Joseph Montecalvo, Jason Chang, Huichun Tai, William W. Lockwood, Victor Martinez, Gregory J. Riely, Charles M. Rudin, Mark G. Kris, Maria E. Arcila, Christopher Matheny, Ryma Benayed, Natasha Rekhtman, Marc Ladanyi and Gopinath Ganji
Cancer Discov April 2 2018 DOI: 10.1158/2159-8290.CD-17-1004

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Response to ERBB3-Directed Targeted Therapy in NRG1-Rearranged Cancers
Alexander Drilon, Romel Somwar, Biju P. Mangatt, Henrik Edgren, Patrice Desmeules, Anja Ruusulehto, Roger S. Smith, Lukas Delasos, Morana Vojnic, Andrew J. Plodkowski, Joshua Sabari, Kenneth Ng, Joseph Montecalvo, Jason Chang, Huichun Tai, William W. Lockwood, Victor Martinez, Gregory J. Riely, Charles M. Rudin, Mark G. Kris, Maria E. Arcila, Christopher Matheny, Ryma Benayed, Natasha Rekhtman, Marc Ladanyi and Gopinath Ganji
Cancer Discov April 2 2018 DOI: 10.1158/2159-8290.CD-17-1004
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