Therapeutically Targeting ErbB3: A Key Node in Ligand-Induced Activation of the ErbB Receptor–PI3K Axis

Sci. Signal., 30 June 2009
Vol. 2, Issue 77, p. ra31
DOI: 10.1126/scisignal.2000352

Therapeutically Targeting ErbB3: A Key Node in Ligand-Induced Activation of the ErbB Receptor–PI3K Axis

  1. Birgit Schoeberl*,
  2. Emily A. Pace*,
  3. Jonathan B. Fitzgerald*,
  4. Brian D. Harms,
  5. Lihui Xu,
  6. Lin Nie,
  7. Bryan Linggi,
  8. Ashish Kalra,
  9. Violette Paragas,
  10. Raghida Bukhalid,
  11. Viara Grantcharova,
  12. Neeraj Kohli,
  13. Kip A. West,
  14. Magdalena Leszczyniecka,
  15. Michael J. Feldhaus,
  16. Arthur J. Kudla, and
  17. Ulrik B. Nielsen
  1. Merrimack Pharmaceuticals, One Kendall Square, Building 700, Cambridge, MA 02139, USA.
  1. To whom correspondence should be addressed. E-mail: unielsen{at}
  • * These authors contributed equally to this work.


The signaling network downstream of the ErbB family of receptors has been extensively targeted by cancer therapeutics; however, understanding the relative importance of the different components of the ErbB network is nontrivial. To explore the optimal way to therapeutically inhibit combinatorial, ligand-induced activation of the ErbB–phosphatidylinositol 3-kinase (PI3K) axis, we built a computational model of the ErbB signaling network that describes the most effective ErbB ligands, as well as known and previously unidentified ErbB inhibitors. Sensitivity analysis identified ErbB3 as the key node in response to ligands that can bind either ErbB3 or EGFR (epidermal growth factor receptor). We describe MM-121, a human monoclonal antibody that halts the growth of tumor xenografts in mice and, consistent with model-simulated inhibitor data, potently inhibits ErbB3 phosphorylation in a manner distinct from that of other ErbB-targeted therapies. MM-121, a previously unidentified anticancer therapeutic designed using a systems approach, promises to benefit patients with combinatorial, ligand-induced activation of the ErbB signaling network that are not effectively treated by current therapies targeting overexpressed or mutated oncogenes.


B. Schoeberl, E. A. Pace, J. B. Fitzgerald, B. D. Harms, L. Xu, L. Nie, B. Linggi, A. Kalra, V. Paragas, R. Bukhalid, V. Grantcharova, N. Kohli, K. A. West, M. Leszczyniecka, M. J. Feldhaus, A. J. Kudla, and U. B. Nielsen, Therapeutically Targeting ErbB3: A Key Node in Ligand-Induced Activation of the ErbB Receptor–PI3K Axis. Sci. Signal. 2, ra31 (2009).

Molecular Pathways: Targeting NRG1 Fusions in Lung Cancer
L. Fernandez-Cuesta, and R. K. Thomas
Clin. Cancer Res. 21, 1989-1994 (1 May 2015)

Colorectal cancer drug target prediction using ontology-based inference and network analysis
C. Tao, J. Sun, W. J. Zheng, J. Chen, and H. Xu
Database 2015, bav015-bav015 (27 March 2015)

A role for the pseudokinase HER3 in the acquired resistance against EGFR- and HER2-directed targeted therapy
J. Claus, G. Patel, T. Ng, and P. J. Parker
Biochm. Soc. Trans. 42, 831-836 (1 August 2014)

Combination of Anti-HER3 Antibody MM-121/SAR256212 and Cetuximab Inhibits Tumor Growth in Preclinical Models of Head and Neck Squamous Cell Carcinoma
N. Jiang, D. Wang, Z. Hu, H. J. C. Shin, G. Qian, M. A. Rahman, H. Zhang, A. R. M. R. Amin, S. Nannapaneni, X. Wang et al.
Molecular Cancer Therapeutics 13, 1826-1836 (1 July 2014)

ERBB3/HER2 Signaling Promotes Resistance to EGFR Blockade in Head and Neck and Colorectal Cancer Models
L. Zhang, C. Castanaro, B. Luan, K. Yang, L. Fan, J. L. Fairhurst, A. Rafique, T. B. Potocky, J. Shan, F. J. Delfino et al.
Molecular Cancer Therapeutics 13, 1345-1355 (1 May 2014)

erbB3 Is an Active Tyrosine Kinase Capable of Homo- and Heterointeractions
M. P. Steinkamp, S. T. Low-Nam, S. Yang, K. A. Lidke, D. S. Lidke, and B. S. Wilson
Mol. Cell. Biol. 34, 965-977 (15 March 2014)

Molecular Pathways: HER3 Targeted Therapy
K. Gala, and S. Chandarlapaty
Clin. Cancer Res. 20, 1410-1416 (15 March 2014)

MM-141, an IGF-IR- and ErbB3-Directed Bispecific Antibody, Overcomes Network Adaptations That Limit Activity of IGF-IR Inhibitors
J. B. Fitzgerald, B. W. Johnson, J. Baum, S. Adams, S. Iadevaia, J. Tang, V. Rimkunas, L. Xu, N. Kohli, R. Rennard et al.
Molecular Cancer Therapeutics 13, 410-425 (1 February 2014)

A Systems Biology Approach to Personalizing Therapeutic Combinations
L. N. Kwong, T. P. Heffernan, and L. Chin
Cancer Discovery 3, 1339-1344 (1 December 2013)

Computational Modeling of ERBB2-Amplified Breast Cancer Identifies Combined ErbB2/3 Blockade as Superior to the Combination of MEK and AKT Inhibitors
D. C. Kirouac, J. Y. Du, J. Lahdenranta, R. Overland, D. Yarar, V. Paragas, E. Pace, C. F. McDonagh, U. B. Nielsen, M. D. Onsum et al.
Sci Signal 6, ra68-ra68 (13 August 2013)

Models of signalling networks - what cell biologists can gain from them and give to them
K. A. Janes, and D. A. Lauffenburger
J. Cell Sci. 126, 1913-1921 (1 May 2013)

Using Partial Least Squares Regression to Analyze Cellular Response Data
P. K. Kreeger, and D. A. Lauffenburger
Sci Signal 6, tr7-tr7 (16 April 2013)

HER3 Overexpression and Survival in Solid Tumors: A Meta-analysis
A. Ocana, F. Vera-Badillo, B. Seruga, A. Templeton, A. Pandiella, and E. Amir
JNCI J Natl Cancer Inst 105, 266-273 (20 February 2013)

Understanding cancer mechanisms through network dynamics
T. M. K. Cheng, S. Gulati, R. Agius, and P. A. Bates
Briefings in Functional Genomics 11, 543-560 (1 November 2012)

Computational Medicine: Translating Models to Clinical Care
R. L. Winslow, N. Trayanova, D. Geman, and M. I. Miller
Sci Transl Med 4, 158rv11-158rv11 (31 October 2012)

Computational Approaches for Analyzing Information Flow in Biological Networks
B. Kholodenko, M. B. Yaffe, and W. Kolch
Sci Signal 5, re1-re1 (17 April 2012)

Antitumor Activity of a Novel Bispecific Antibody That Targets the ErbB2/ErbB3 Oncogenic Unit and Inhibits Heregulin-Induced Activation of ErbB3
C. F. McDonagh, A. Huhalov, B. D. Harms, S. Adams, V. Paragas, S. Oyama, B. Zhang, L. Luus, R. Overland, S. Nguyen et al.
Molecular Cancer Therapeutics 11, 582-593 (1 March 2012)

Monoclonal antibodies in cancer therapy
A. M. Scott, J. P. Allison, and J. D. Wolchok
Cancer Immun 12, 14-14 (1 January 2012)

Reduction of Complex Signaling Networks to a Representative Kernel
J.-R. Kim, J. Kim, Y.-K. Kwon, H.-Y. Lee, P. Heslop-Harrison, and K.-H. Cho
Sci Signal 4, ra35-ra35 (31 May 2011)

Combining phage and staphylococcal surface display for generation of ErbB3-specific Affibody molecules
N. Kronqvist, M. Malm, L. Gostring, E. Gunneriusson, M. Nilsson, I. Hoiden Guthenberg, L. Gedda, F. Y. Frejd, S. Stahl, J. Lofblom et al.
Protein Eng Des Sel 24, 385-396 (1 April 2011)

Receptor Tyrosine Kinase Coactivation Networks in Cancer
A. M. Xu, and P. H. Huang
Cancer Res. 70, 3857-3860 (15 May 2010)

An ErbB3 Antibody, MM-121, Is Active in Cancers with Ligand-Dependent Activation
B. Schoeberl, A. C. Faber, D. Li, M.-C. Liang, K. Crosby, M. Onsum, O. Burenkova, E. Pace, Z. Walton, L. Nie et al.
Cancer Res. 70, 2485-2494 (15 March 2010)

Science Signaling Podcast: 5 January 2010
M. B. Yaffe, and A. M. VanHook
Sci Signal 3, pc1-pc1 (5 January 2010)

2009: Signaling Breakthroughs of the Year
E. M. Adler, and A. M. VanHook
Sci Signal 3, eg1-eg1 (5 January 2010)

Cancer systems biology: a network modeling perspective
P. K. Kreeger, and D. A. Lauffenburger
Carcinogenesis 31, 2-8 (1 January 2010)

Science Signaling Podcast: 30 June 2009
U. B. Nielsen, and A. M. VanHook
Sci Signal 2, pc12-pc12 (30 June 2009)

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882