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

[Rich66]

When I read that, unclear to me whether they are talking specifically about using Herceptin/Tykerb combination or either as monotherapy.

In any case..it seems like her3 inhibition may be helpful.

An FDA approved Her3 inhibitor:

Int J Cancer. 2008 Dec 15;123(12):2939-49.
Chemoresistant tumor cell lines display altered epidermal growth factor receptor and HER3 signaling and enhanced sensitivity to gefitinib.

Servidei T, Riccardi A, Mozzetti S, Ferlini C, Riccardi R.
Department of Pediatric Oncology, Catholic University, Rome, Italy. tservidei@rm.unicatt.it
Abstract

Deregulated signaling through the epidermal growth factor receptor (EGFR) is involved in chemoresistance. To identify the molecular determinants of sensitivity to the EGFR inhibitor gefitinib (Iressa, ZD1839) in chemoresistance, we compared the response of matched chemosensitive and chemoresistant glioma and ovarian cancer cell lines. We found that chemoresistant cell lines were 2- to 3-fold more sensitive to gefitinib growth-inhibitory effects, because of decreased proliferation rather than survival. Sensitivity to gefitinib correlated with overexpression and constitutive phosphorylation of HER2 and HER3, but not EGFR, altered HER ligand expression, and enhanced activation of EGF-triggered EGFR pathway. No activating mutations were found in EGFR. Gefitinib fully inhibited EGF-induced and constitutive Akt activation only in chemoresistant cells. In parallel, gefitinib downregulated constitutively phosphorylated HER2 and HER3, and activated GSK3beta with a concomitant degradation of cyclin D1. Ectopically overexpressed HER2 on its own was insufficient to sensitize chemonaive cells to gefitinib. pHER3 coimmunoprecipitated with p85-PI3K in chemoresistant cells and gefitinib dissociated these complexes. siRNA-mediated inhibition of HER3 decreased constitutive activation of Akt and sensitivity to gefitinib in chemoresistant cells. Our study indicates that in chemoresistant cells gefitinib inhibits both an enhanced EGF-triggered pathway and a constitutive HER3-mediated Akt activation, indicating that inhibition of HER3 together with that of EGFR could be relevant in chemorefractory tumors. Furthermore, in combination experiments gefitinib enhanced the effects of coadministered drugs more in chemoresistant than chemosensitive ovarian cancer cells. Combined treatment might be therapeutically beneficial in chemoresistant tumors from ovary and likely from other tissues. (c) 2008 Wiley-Liss, Inc.

PMID: 18803287 [PubMed - indexed for MEDLINE]




Another in unknown stage of development:


Mol Pharmacol. 2005 Aug;68(2):502-10. Epub 2005 May 20.
Kahalalide F induces necrosis-like cell death that involves depletion of ErbB3 and inhibition of Akt signaling.

Janmaat ML, Rodriguez JA, Jimeno J, Kruyt FA, Giaccone G.
Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, PO Box 7057, 1007MB Amsterdam, The Netherlands. g.giaccone@vumc.nl



Abstract

Kahalalide F (KF) is a novel marine-derived antitumor agent that is currently undergoing phase II clinical trials. The mechanism of action of KF is not well understood. In line with previous reports, we show that KF caused rapid and potent cytotoxicity in the breast cancer cell lines SKBR3 and BT474, characterized by cytoplasmic swelling and DNA clumping. Several markers of caspase-dependent apoptosis, such as phosphatidyl-serine externalization, cytochrome c release, and caspase-3 and poly-(ADP-ribose) polymerase cleavage were negative after KF exposure. Inhibitors of caspases or cathepsins failed to protect against KF cytotoxicity. Altogether, these data indicate that KF-induced cell death is a necrosis-like process. The sensitivity to KF in a panel of human tumor cell lines derived from breast (SKBR3, BT474, and MCF7), vulval (A431), non-small-cell lung (H460, A549, SW1573, and H292), and hepatic (Skhep1, HepG2, and Hep3B) carcinomas positively correlated with ErbB3 (HER3) protein levels. A KF-resistant subline of colon carcinoma cells, HT29/KF, expressed significantly reduced levels of all ErbB receptors, but short-term KF exposure of sensitive cell lines such as SKBR3 selectively induced down-regulation of ErbB3. On the other hand, stable transfection of an ErbB3-expressing plasmid increased the KF sensitivity of H460 cells, the most resistant cell line in our panel. Finally, we found that KF efficiently inhibited the phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway in sensitive cell lines and that ectopic expression of a constitutively active Akt mutant reduced KF cytotoxicity in this cell line. In summary, our results identify ErbB3 and the downstream PI3K-Akt pathway as important determinants of the cytotoxic activity of KF in vitro.

PMID: 15908515 [PubMed - indexed for MEDLINE]Free Article






Often helpful to "Follow the patent":


Activated her3 as a marker for predicting therapeutic efficacy description/claims
http://www.freshpatents.com/-dt20100...0100047829.php

[Darlene Denise]

Maybe GDC 0941 will be the ticket?