Abstract
HER2/HER3 dimerization resulting from overexpression of HER2 or neuregulin (NRG1) in cancer leads to HER3-mediated oncogenic activation of phosphoinositide 3-kinase (PI3K) signaling. Although ligand-blocking HER3 antibodies inhibit NRG1-driven tumor growth, they are ineffective against HER2-driven tumor growth because HER2 activates HER3 in a ligand-independent manner. In this study, we describe a novel HER3 monoclonal antibody (LJM716) that can neutralize multiple modes of HER3 activation, making it a superior candidate for clinical translation as a therapeutic candidate. LJM716 was a potent inhibitor of HER3/AKT phosphorylation and proliferation in HER2-amplified and NRG1-expressing cancer cells, and it displayed single-agent efficacy in tumor xenograft models. Combining LJM716 with agents that target HER2 or EGFR produced synergistic antitumor activity in vitro and in vivo. In particular, combining LJM716 with trastuzumab produced a more potent inhibition of signaling and cell proliferation than trastuzumab/pertuzumab combinations with similar activity in vivo. To elucidate its mechanism of action, we solved the structure of LJM716 bound to HER3, finding that LJM716 bound to an epitope, within domains 2 and 4, that traps HER3 in an inactive conformation. Taken together, our findings establish that LJM716 possesses a novel mechanism of action that, in combination with HER2- or EGFR-targeted agents, may leverage their clinical efficacy in ErbB-driven cancers.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 6024-6035 |
| Number of pages | 12 |
| Journal | Cancer Research |
| Volume | 73 |
| Issue number | 19 |
| DOIs | |
| State | Published - Oct 1 2013 |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
An antibody that locks HER3 in the inactive conformation inhibits tumor growth driven by HER2 or neuregulin. / Garner, Andrew P.; Bialucha, Carl U.; Sprague, Elizabeth R.; Garrett, Joan T.; Sheng, Qing; Li, Sharon; Sineshchekova, Olga; Saxena, Parmita; Sutton, Cammie R.; Chen, Dongshu; Chen, Yan; Wang, Huiqin; Liang, Jinsheng; Das, Rita; Mosher, Rebecca; Gu, Jian; Huang, Alan; Haubst, Nicole; Zehetmeier, Carolin; Haberl, Manuela; Elis, Winfried; Kunz, Christian; Heidt, Analeah B.; Herlihy, Kara; Murtie, Joshua; Schuller, Alwin; Arteaga, Carlos L.; Sellers, William R.; Ettenberg, Seth A.
In: Cancer Research, Vol. 73, No. 19, 01.10.2013, p. 6024-6035.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - An antibody that locks HER3 in the inactive conformation inhibits tumor growth driven by HER2 or neuregulin
AU - Garner, Andrew P.
AU - Bialucha, Carl U.
AU - Sprague, Elizabeth R.
AU - Garrett, Joan T.
AU - Sheng, Qing
AU - Li, Sharon
AU - Sineshchekova, Olga
AU - Saxena, Parmita
AU - Sutton, Cammie R.
AU - Chen, Dongshu
AU - Chen, Yan
AU - Wang, Huiqin
AU - Liang, Jinsheng
AU - Das, Rita
AU - Mosher, Rebecca
AU - Gu, Jian
AU - Huang, Alan
AU - Haubst, Nicole
AU - Zehetmeier, Carolin
AU - Haberl, Manuela
AU - Elis, Winfried
AU - Kunz, Christian
AU - Heidt, Analeah B.
AU - Herlihy, Kara
AU - Murtie, Joshua
AU - Schuller, Alwin
AU - Arteaga, Carlos L.
AU - Sellers, William R.
AU - Ettenberg, Seth A.
PY - 2013/10/1
Y1 - 2013/10/1
N2 - HER2/HER3 dimerization resulting from overexpression of HER2 or neuregulin (NRG1) in cancer leads to HER3-mediated oncogenic activation of phosphoinositide 3-kinase (PI3K) signaling. Although ligand-blocking HER3 antibodies inhibit NRG1-driven tumor growth, they are ineffective against HER2-driven tumor growth because HER2 activates HER3 in a ligand-independent manner. In this study, we describe a novel HER3 monoclonal antibody (LJM716) that can neutralize multiple modes of HER3 activation, making it a superior candidate for clinical translation as a therapeutic candidate. LJM716 was a potent inhibitor of HER3/AKT phosphorylation and proliferation in HER2-amplified and NRG1-expressing cancer cells, and it displayed single-agent efficacy in tumor xenograft models. Combining LJM716 with agents that target HER2 or EGFR produced synergistic antitumor activity in vitro and in vivo. In particular, combining LJM716 with trastuzumab produced a more potent inhibition of signaling and cell proliferation than trastuzumab/pertuzumab combinations with similar activity in vivo. To elucidate its mechanism of action, we solved the structure of LJM716 bound to HER3, finding that LJM716 bound to an epitope, within domains 2 and 4, that traps HER3 in an inactive conformation. Taken together, our findings establish that LJM716 possesses a novel mechanism of action that, in combination with HER2- or EGFR-targeted agents, may leverage their clinical efficacy in ErbB-driven cancers.
AB - HER2/HER3 dimerization resulting from overexpression of HER2 or neuregulin (NRG1) in cancer leads to HER3-mediated oncogenic activation of phosphoinositide 3-kinase (PI3K) signaling. Although ligand-blocking HER3 antibodies inhibit NRG1-driven tumor growth, they are ineffective against HER2-driven tumor growth because HER2 activates HER3 in a ligand-independent manner. In this study, we describe a novel HER3 monoclonal antibody (LJM716) that can neutralize multiple modes of HER3 activation, making it a superior candidate for clinical translation as a therapeutic candidate. LJM716 was a potent inhibitor of HER3/AKT phosphorylation and proliferation in HER2-amplified and NRG1-expressing cancer cells, and it displayed single-agent efficacy in tumor xenograft models. Combining LJM716 with agents that target HER2 or EGFR produced synergistic antitumor activity in vitro and in vivo. In particular, combining LJM716 with trastuzumab produced a more potent inhibition of signaling and cell proliferation than trastuzumab/pertuzumab combinations with similar activity in vivo. To elucidate its mechanism of action, we solved the structure of LJM716 bound to HER3, finding that LJM716 bound to an epitope, within domains 2 and 4, that traps HER3 in an inactive conformation. Taken together, our findings establish that LJM716 possesses a novel mechanism of action that, in combination with HER2- or EGFR-targeted agents, may leverage their clinical efficacy in ErbB-driven cancers.
UR - http://www.scopus.com/inward/record.url?scp=84885024224&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84885024224&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-13-1198
DO - 10.1158/0008-5472.CAN-13-1198
M3 - Article
C2 - 23928993
AN - SCOPUS:84885024224
VL - 73
SP - 6024
EP - 6035
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0099-7013
IS - 19
ER -