Oncogenic ERBB3 Mutations in Human Cancers

Bijay S. Jaiswal, Noelyn M. Kljavin, Eric W. Stawiski, Emily Chan, Chaitali Parikh, Steffen Durinck, Subhra Chaudhuri, Kanan Pujara, Joseph Guillory, Kyle A. Edgar, Vasantharajan Janakiraman, Rolf Peter Scholz, Krista Bowman, Maria Lorenzo, Hong Li, Jiansheng Wu, Wenlin Yuan, Brock A. Peters, Zhengyan Kan, Jeremy StinsonMichelle Mak, Zora Modrusan, Charles Eigenbrot, Ron Firestein, Howard M. Stern, Krishnaraj Rajalingam, Gabriele Schaefer, Mark A. Merchant, Mark X. Sliwkowski, Frederic J. deSauvage, Somasekar Seshagiri

Research output: Contribution to journalArticleResearchpeer-review

221 Citations (Scopus)

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 languageEnglish
Pages (from-to)603-617
Number of pages15
JournalCancer Cell
Volume23
Issue number5
DOIs
Publication statusPublished - 13 May 2013
Externally publishedYes

Cite this

Jaiswal, B. S., Kljavin, N. M., Stawiski, E. W., Chan, E., Parikh, C., Durinck, S., ... Seshagiri, S. (2013). Oncogenic ERBB3 Mutations in Human Cancers. Cancer Cell, 23(5), 603-617. https://doi.org/10.1016/j.ccr.2013.04.012
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. / Oncogenic ERBB3 Mutations in Human Cancers. In: Cancer Cell. 2013 ; Vol. 23, No. 5. pp. 603-617.
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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. ",
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Jaiswal, BS, Kljavin, NM, Stawiski, EW, Chan, E, Parikh, C, Durinck, S, Chaudhuri, S, Pujara, K, Guillory, J, Edgar, KA, Janakiraman, V, Scholz, RP, Bowman, K, Lorenzo, M, Li, H, Wu, J, Yuan, W, Peters, BA, Kan, Z, Stinson, J, Mak, M, Modrusan, Z, Eigenbrot, C, Firestein, R, Stern, HM, Rajalingam, K, Schaefer, G, Merchant, MA, Sliwkowski, MX, deSauvage, FJ & Seshagiri, S 2013, 'Oncogenic ERBB3 Mutations in Human Cancers', Cancer Cell, vol. 23, no. 5, pp. 603-617. https://doi.org/10.1016/j.ccr.2013.04.012

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 journalArticleResearchpeer-review

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AU - Li, Hong

AU - Wu, Jiansheng

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AU - Mak, Michelle

AU - Modrusan, Zora

AU - Eigenbrot, Charles

AU - Firestein, Ron

AU - Stern, Howard M.

AU - Rajalingam, Krishnaraj

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AU - Merchant, Mark A.

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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. 

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Jaiswal BS, Kljavin NM, Stawiski EW, Chan E, Parikh C, Durinck S et al. Oncogenic ERBB3 Mutations in Human Cancers. Cancer Cell. 2013 May 13;23(5):603-617. https://doi.org/10.1016/j.ccr.2013.04.012