her3 may upregulate if only herceptin, tykerb used in combination

[Lani]

a new paper hot off the press claims her3 is not without functional phosphorylation at its intracellular domain site, just weak and that treatment with herceptin, tykerb may develop resistance if her3 is not blocked also

"Indeed, ErbB3 autophosphorylation in vitro is not inhibited by lapatinib or by the EGFR inhibitors gefitinib or erlotinib (Fig. S7), leaving open the possibility that ErbB3 kinase activity promotes resistance to growth inhibition by EGFR/ ErbB2-targeted drugs. If this is the case, selective inhibition of the ErbB3 kinase could be an important additional therapeutic strategy."

Proc Natl Acad Sci U S A. 2010 Apr 27;107(17):7692-7. Epub 2010 Mar 29.
ErbB3/HER3 intracellular domain is competent to bind ATP and catalyze autophosphorylation.
Shi F, Telesco SE, Liu Y, Radhakrishnan R, Lemmon MA.

Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Comment in:

Proc Natl Acad Sci U S A. 2010 May 4;107(18):8047-8.
Abstract
ErbB3/HER3 is one of four members of the human epidermal growth factor receptor (EGFR/HER) or ErbB receptor tyrosine kinase family. ErbB3 binds neuregulins via its extracellular region and signals primarily by heterodimerizing with ErbB2/HER2/Neu. A recently appreciated role for ErbB3 in resistance of tumor cells to EGFR/ErbB2-targeted therapeutics has made it a focus of attention. However, efforts to inactivate ErbB3 therapeutically in parallel with other ErbB receptors are challenging because its intracellular kinase domain is thought to be an inactive pseudokinase that lacks several key conserved (and catalytically important) residues-including the catalytic base aspartate. We report here that, despite these sequence alterations, ErbB3 retains sufficient kinase activity to robustly trans-autophosphorylate its intracellular region--although it is substantially less active than EGFR and does not phosphorylate exogenous peptides. The ErbB3 kinase domain binds ATP with a K(d) of approximately 1.1 microM. We describe a crystal structure of ErbB3 kinase bound to an ATP analogue, which resembles the inactive EGFR and ErbB4 kinase domains (but with a shortened alphaC-helix). Whereas mutations that destabilize this configuration activate EGFR and ErbB4 (and promote EGFR-dependent lung cancers), a similar mutation conversely inactivates ErbB3. Using quantum mechanics/molecular mechanics simulations, we delineate a reaction pathway for ErbB3-catalyzed phosphoryl transfer that does not require the conserved catalytic base and can be catalyzed by the "inactive-like" configuration observed crystallographically. These findings suggest that ErbB3 kinase activity within receptor dimers may be crucial for signaling and could represent an important therapeutic target.

PMID: 20351256