+ Resolve Article
+ Follow Us
Follow on FacebookFollow on Facebook
Follow on TwitterFollow on Twitter

+ Translate
+ Subscribe to Site Feed
GeoScience Most Shared ContentMost Shared Content

Activation of HER3 interferes with antitumor effects of Axl receptor tyrosine kinase inhibitors: suggestion of combination therapy

, : Activation of HER3 interferes with antitumor effects of Axl receptor tyrosine kinase inhibitors: suggestion of combination therapy. Neoplasia 16(4): 301-318

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-α 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.


PMID: 24862757

DOI: 10.1016/j.neo.2014.03.009

Other references

Dayal Drager R.; Kumar S.; Decrind C.; Lambert P H., 1987: Identification of a non variant circulating human malaria antigen in patient serum. International Archives of Allergy & Applied Immunology 83(SUPPL 1): 2

Giertsen, J.C., 1960: The reliability of macroscopical grading of atherosclerosis. Acta Pathologica et Microbiologica Scandinavica 50: 355-368

Savoie A., 1979: Equipment for the collection of tissue eating ciliates. Journal of Protozoology 26(3 PART 1): 69A

Komarov S.G., 1940: Otsenka neftyanykh mestorozhdeniy po dannym karottazha. Estimation of oil-bearing beds by electrical coring data. The resistance values primarily represent the extent of saturation of the oil-bearing beds.

Borojevic, K., 1971: Genetic structure of populations of Triticum aestivum ssp. vulgare after mutagenic treatments. The effects of mutagenesis, induced by various agents, on the population structure are summarized. The usefulness of selection after such treatment as a breeding technique is discussed in the light of genetic variability and changes in population...

Muller R.N., 1982: Vegetation patterns in the mixed mesophytic forest of eastern kentucky usa. Two forest stands representing typical old-growth mixed mesophytic forest and 35-yr-old second-growth in Letcher County, southeastern Kentucky, were studied to compare structure and composition, and to determine patterns of species distribution in...

Prop, N.; Ebels, I., 1968: Effects of sheep and young calf pineal extracts and continuous light on the pineal gland, the gonads and the oestrous cycle of the rat. Compared with controls on a normal day/night laboratory regime, on continuous light for 70-150 days had a high mean percentage of oestrus smears (81 v 39), a significant increase in uterine weight, and a significant decrease in ovarian weight. The...

Sturgiss, E.; Haesler, E.; Elmitt, N.; van Weel, C.; Douglas, K., 2017: Increasing general practitioners' confidence and self-efficacy in managing obesity: a mixed methods study. Internationally, general practitioners (GPs) are being encouraged to take an active role in the care of their patients with obesity, but as yet there are few tools for them to implement within their clinics. This study assessed the self-efficacy a...

Wurtz, B.; Mursch, R., 1951: Modifications of biochemical and morphological properties of lactic bacilli of silage. Comptes Rendus Hebdomadaires des Seances de L'academie des Sciences 233(4): 327-328

Antonietti A., 1991: Why does mental visualization facilitate problem solving?. Logie, R H And M Denis (Ed ) Advances in Psychology, Vol 80 Mental Images in Human Cognition Xvi+433p Elsevier Science Publishers B V : Amsterdam, Netherlands; (Dist in The Usa And Canada By Elsevier Science Publishing Co , Inc : New York, New York) Illus 211-228