Abstract
The human epidermal growth factor receptor (HER) family of tyrosine kinases is deregulated in multiple cancers either through amplification, overexpression, or mutation. ERBB3/HER3, the only member with an impaired kinase domain, although amplified or overexpressed in some cancers, has not been reported to carry oncogenic mutations. Here, we report the identification of ERBB3 somatic mutations in ~11% of colon and gastric cancers. We found that the ERBB3 mutants transformed colonic and breast epithelial cells in a ligand-independent manner. However, the mutant ERBB3 oncogenic activity was dependent on kinase-active ERBB2. Furthermore, we found that anti-ERBB antibodies and small molecule inhibitors effectively blocked mutant ERBB3-mediated oncogenic signaling and disease progression invivo.
| Original language | English |
|---|---|
| Pages (from-to) | 603-617 |
| Number of pages | 15 |
| Journal | Cancer Cell |
| Volume | 23 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 13 May 2013 |
| Externally published | Yes |
Cite this
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Oncogenic ERBB3 Mutations in Human Cancers. / Jaiswal, Bijay S.; Kljavin, Noelyn M.; Stawiski, Eric W.; Chan, Emily; Parikh, Chaitali; Durinck, Steffen; Chaudhuri, Subhra; Pujara, Kanan; Guillory, Joseph; Edgar, Kyle A.; Janakiraman, Vasantharajan; Scholz, Rolf Peter; Bowman, Krista; Lorenzo, Maria; Li, Hong; Wu, Jiansheng; Yuan, Wenlin; Peters, Brock A.; Kan, Zhengyan; Stinson, Jeremy; Mak, Michelle; Modrusan, Zora; Eigenbrot, Charles; Firestein, Ron; Stern, Howard M.; Rajalingam, Krishnaraj; Schaefer, Gabriele; Merchant, Mark A.; Sliwkowski, Mark X.; deSauvage, Frederic J.; Seshagiri, Somasekar.
In: Cancer Cell, Vol. 23, No. 5, 13.05.2013, p. 603-617.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Oncogenic ERBB3 Mutations in Human Cancers
AU - Jaiswal, Bijay S.
AU - Kljavin, Noelyn M.
AU - Stawiski, Eric W.
AU - Chan, Emily
AU - Parikh, Chaitali
AU - Durinck, Steffen
AU - Chaudhuri, Subhra
AU - Pujara, Kanan
AU - Guillory, Joseph
AU - Edgar, Kyle A.
AU - Janakiraman, Vasantharajan
AU - Scholz, Rolf Peter
AU - Bowman, Krista
AU - Lorenzo, Maria
AU - Li, Hong
AU - Wu, Jiansheng
AU - Yuan, Wenlin
AU - Peters, Brock A.
AU - Kan, Zhengyan
AU - Stinson, Jeremy
AU - Mak, Michelle
AU - Modrusan, Zora
AU - Eigenbrot, Charles
AU - Firestein, Ron
AU - Stern, Howard M.
AU - Rajalingam, Krishnaraj
AU - Schaefer, Gabriele
AU - Merchant, Mark A.
AU - Sliwkowski, Mark X.
AU - deSauvage, Frederic J.
AU - Seshagiri, Somasekar
PY - 2013/5/13
Y1 - 2013/5/13
N2 - The human epidermal growth factor receptor (HER) family of tyrosine kinases is deregulated in multiple cancers either through amplification, overexpression, or mutation. ERBB3/HER3, the only member with an impaired kinase domain, although amplified or overexpressed in some cancers, has not been reported to carry oncogenic mutations. Here, we report the identification of ERBB3 somatic mutations in ~11% of colon and gastric cancers. We found that the ERBB3 mutants transformed colonic and breast epithelial cells in a ligand-independent manner. However, the mutant ERBB3 oncogenic activity was dependent on kinase-active ERBB2. Furthermore, we found that anti-ERBB antibodies and small molecule inhibitors effectively blocked mutant ERBB3-mediated oncogenic signaling and disease progression invivo.
AB - The human epidermal growth factor receptor (HER) family of tyrosine kinases is deregulated in multiple cancers either through amplification, overexpression, or mutation. ERBB3/HER3, the only member with an impaired kinase domain, although amplified or overexpressed in some cancers, has not been reported to carry oncogenic mutations. Here, we report the identification of ERBB3 somatic mutations in ~11% of colon and gastric cancers. We found that the ERBB3 mutants transformed colonic and breast epithelial cells in a ligand-independent manner. However, the mutant ERBB3 oncogenic activity was dependent on kinase-active ERBB2. Furthermore, we found that anti-ERBB antibodies and small molecule inhibitors effectively blocked mutant ERBB3-mediated oncogenic signaling and disease progression invivo.
UR - http://www.scopus.com/inward/record.url?scp=84877839648&partnerID=8YFLogxK
U2 - 10.1016/j.ccr.2013.04.012
DO - 10.1016/j.ccr.2013.04.012
M3 - Article
C2 - 23680147
AN - SCOPUS:84877839648
VL - 23
SP - 603
EP - 617
JO - Cancer Cell
JF - Cancer Cell
SN - 1535-6108
IS - 5
ER -