English
 
User Manual Privacy Policy Disclaimer Contact us
  Advanced SearchBrowse

Item

ITEM ACTIONSEXPORT
  Activation of HER3 Interferes with Antitumor Effects of Axl Receptor Tyrosine Kinase Inhibitors: Suggestion of Combination Therapy

Torka, R., Penzes, K., Gusenbauer, S., Baumann, C., Szabadkai, I., Orfi, L., et al. (2014). Activation of HER3 Interferes with Antitumor Effects of Axl Receptor Tyrosine Kinase Inhibitors: Suggestion of Combination Therapy. NEOPLASIA, 16(4), 301-318. doi:10.1016/j.neo.2014.03.009.

Item is

Basic

show hide
Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0019-D0B2-2 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0019-D0B3-F
Genre: Journal Article

Files

show Files
hide Files
:
1-s2.0-S1476558614000281-main.pdf (Any fulltext), 2MB
Name:
1-s2.0-S1476558614000281-main.pdf
Description:
-
Visibility:
Public
MIME-Type / Checksum:
application/pdf / [MD5]
Technical Metadata:
Copyright Date:
-
Copyright Info:
open access article
License:
-

Locators

show

Creators

show
hide
 Creators:
Torka, Robert1, Author              
Penzes, Kinga1, Author              
Gusenbauer, Simone1, Author              
Baumann, Christine2, Author
Szabadkai, Istvan2, Author
Orfi, Laszlo2, Author
Keri, György2, Author
Ullrich, Axel1, Author              
Affiliations:
1Ullrich, Axel / Molecular Biology, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565172              
2external, ou_persistent22              

Content

show
hide
Free keywords: MYELOID-LEUKEMIA CELLS; BREAST-CANCER; PROLONGS SURVIVAL; PI3K INHIBITORS; ERBB RECEPTORS; GROWTH-ARREST; TUMOR; EXPRESSION; RESISTANCE; EGFR
 Abstract: The Axl receptor tyrosine kinase (RTK) has been established as a strong candidate for targeted therapy of cancer. However, the benefits of targeted therapies are limited due to acquired resistance and activation of alternative RTKs. Therefore, we asked if cancer cells are able to overcome targeted Axl therapies. Here, we demonstrate that inhibition of Axl by short interfering RNA or the tyrosine kinase inhibitor (TKI) BMS777607 induces the expression of human epidermal growth factor receptor 3 (HER3) and the neuregulin 1(NRG1)-dependent phosphorylation of HER3 in MDA-MB231 and Ovcar8 cells. Moreover, analysis of 20 Axl-expressing cancer cell lines of different tissue origin indicates a low basal phosphorylation of RAC-alpha serine/threonine-protein kinase (AKT) as a general requirement for HER3 activation on Axl inhibition. Consequently, phosphorylation of AKT arises as an independent biomarker for Axl treatment. Additionally, we introduce phosphorylation of HER3 as an independent pharmacodynamic biomarker for monitoring of anti-Axl therapy response. Inhibition of cell viability by BMS777607 could be rescued by NRG1-dependent activation of HER3, suggesting an escape mechanism by tumor microenvironment. The Axl-TKI MPCD84111 simultaneously blocked Axl and HER2/3 signaling and thereby prohibited HER3 feedback activation. Furthermore, dual inhibition of Axl and HER2/3 using BMS777607 and lapatinib led to a significant inhibition of cell viability in Axl-expressing MDA-MB231 and Ovcar8 cells. Therefore, we conclude that, in patient cohorts with expression of Axl and low basal activity of AKT, a combined inhibition of Axl and HER2/3 kinase would be beneficial to overcome acquired resistance to Axl-targeted therapies.

Details

show
hide
Language(s): eng - English
 Dates: 2014-04
 Publication Status: Published in print
 Pages: 18
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: ISI: 000336524200003
DOI: 10.1016/j.neo.2014.03.009
 Degree: -

Event

show

Legal Case

show

Project information

show

Source 1

show
hide
Title: NEOPLASIA
Source Genre: Journal
 Creator(s):
Affiliations:
Publ. Info: 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA : ELSEVIER SCIENCE INC
Pages: - Volume / Issue: 16 (4) Sequence Number: - Start / End Page: 301 - 318 Identifier: ISSN: 1522-8002