Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 686-695 |
| Number of pages | 10 |
| Journal | Cancer Discovery |
| Volume | 8 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - Jun 2018 |
| Externally published | Yes |
Bibliographical note
Funding Information:We would like to thank all our patients, their families, and the site staff for their participation and contributions to this study. We also acknowledge BioWa, Inc. (U.S. subsidiary of Kyowa Hakko Kirin Co., Ltd.) for their POTELLIGENT Technology and COMPLEGENT Technology in developing GSK2849330, an ADCC- and CDC-enhanced anti-ERBB3 mAb. Baseline characterization of the OV-10-0050 PDX model was carried out at WuXi AppTec Co., Ltd. (Shanghai, China). A. Drilon, G.J. Riely, C.M. Rudin, and M.G. Kris are supported by the NIH by NCI Cancer Support Grant P30 CA008748, which did not directly fund study costs. The NCT01966445 study was sponsored by GlaxoSmithKline.
Funding Information:
A. Ruusulehto has ownership interest (including patents) in MediSapiens Ltd. G.J. Riely reports receiving commercial research support from Ariad/Takeda, Novartis, Pfizer, and Roche/Genen-tech. M.G. Kris is a consultant/advisory board member for Astra-Zeneca. No potential conflicts of interest were disclosed by the other authors.
Funding Information:
We would like to thank all our patients, their families, and the site staff for their participation and contributions to this study. We also acknowledge BioWa, Inc. (U.S. subsidiary of Kyowa Hakko Kirin Co., Ltd.) for their POTELLIGENT Technology and COMPLEGENT Technology in developing GSK2849330, an ADCC-and CDC-enhanced anti-ERBB3 mAb. Baseline characterization of the OV-10-0050 PDX model was carried out at WuXi AppTec Co., Ltd. (Shanghai, China). A. Drilon, G.J. Riely, C.M. Rudin, and M.G. Kris are supported by the NIH by NCI Cancer Support Grant P30 CA008748, which did not directly fund study costs. The NCT01966445 study was sponsored by GlaxoSmithKline.
Publisher Copyright:
© 2018 American Association for Cancer Research.
ASJC Scopus Subject Areas
- Oncology
