Response to ERBB3-directed targeted therapy in NRG1 -rearranged cancers Academic Article uri icon

Overview

MeSH Major

  • Autoantibodies
  • Carcinoma, Small Cell
  • Lung Neoplasms
  • Neurons
  • Paraneoplastic Syndromes

abstract

  • © 2018 American Association for Cancer Research. NRG1 rearrangements are oncogenic drivers that are enriched in invasive mucinous adenocarcinomas (IMA) 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 mAb therapy (GSK2849330) in an exceptional responder with an NRG1 -rearranged IMA on a phase I trial (NCT01966445). In contrast, response was not achieved with anti-ERBB2 therapy (afatinib) in four patients with NRG1 -rearranged IMA (including the index patient post-GSK2849330). Although in vitro data supported the use of either ERBB3 or ERBB2 inhibition, these clinical results were consistent with more profound antitumor 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, identifi ed NRG1 rearrangements with novel fusion partners in multiple histologies, including breast, head and neck, renal, lung, ovarian, pancreatic, prostate, and uterine cancers. SIGnIFICAnCE: This series highlights the utility of ERBB3 inhibition as a novel treatment paradigm for NRG1 -rearranged cancers. In addition, it provides preliminary evidence that ERBB3 inhibition may be more optimal than ERBB2 inhibition. The identifi cation of NRG1 rearrangements across various solid tumors supports a basket trial approach to drug development.

publication date

  • June 2018

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC5984717

Digital Object Identifier (DOI)

  • 10.1158/2159-8290.CD-17-1004

PubMed ID

  • 29610121

Additional Document Info

start page

  • 686

end page

  • 695

volume

  • 8

number

  • 6