Combinatorial targeting of FGF and ErbB receptors blocks growth and metastatic spread of breast cancer models

Introduction Targeting receptor tyrosine kinases (RTKs) with kinase inhibitors is a clinically validated anti-cancer approach. However, blocking one signaling pathway is often not sufficient to cause tumor regression and the effectiveness of individual inhibitors is often short-lived. As alterations...

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Vydáno v:	Breast cancer research : BCR Ročník 15; číslo 1; s. R8
Hlavní autoři:	Issa, Amine, Gill, Jason W, Heideman, Marinus R, Sahin, Ozgur, Wiemann, Stefan, Dey, Julien H, Hynes, Nancy E
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London BioMed Central 23.01.2013
Témata:	Animals Biomedical and Life Sciences Biomedicine Breast Neoplasms - drug therapy Breast Neoplasms - genetics Breast Neoplasms - pathology Cancer Research Cell Proliferation - drug effects ErbB Receptors - antagonists & inhibitors ErbB Receptors - genetics Female Gene Expression Regulation, Neoplastic - drug effects Humans Imidazoles - administration & dosage Mice Molecular Targeted Therapy Oncology Phosphatidylinositol 3-Kinases - administration & dosage Phosphatidylinositol 3-Kinases - genetics Protein Kinase Inhibitors - administration & dosage Proto-Oncogene Proteins c-akt - genetics Purines - administration & dosage Quinolines - administration & dosage Receptors, Fibroblast Growth Factor - antagonists & inhibitors Receptors, Fibroblast Growth Factor - genetics Research Article Signal Transduction - drug effects Surgical Oncology TOR Serine-Threonine Kinases - genetics Xenograft Model Antitumor Assays ErbB Receptor Fibroblast Growth Factor Receptor Inhibitor Fibroblast Growth Factor Receptor 67NR Cell Circulate Tumor Cell
ISSN:	1465-542X, 1465-5411, 1465-542X
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Shrnutí:	Introduction Targeting receptor tyrosine kinases (RTKs) with kinase inhibitors is a clinically validated anti-cancer approach. However, blocking one signaling pathway is often not sufficient to cause tumor regression and the effectiveness of individual inhibitors is often short-lived. As alterations in fibroblast growth factor receptor (FGFR) activity have been implicated in breast cancer, we examined in breast cancer models with autocrine FGFR activity the impact of targeting FGFRs in vivo with a selective kinase inhibitor in combination with an inhibitor of PI3K/mTOR or with a pan-ErbB inhibitor. Methods Using 4T1 or 67NR models of basal-like breast cancer, tumor growth was measured in mice treated with an FGFR inhibitor (dovitinib/TKI258), a PI3K/mTOR inhibitor (NVP-BEZ235) or a pan-ErbB inhibitor (AEE788) individually or in combination. To uncover mechanisms underlying inhibitor action, signaling pathway activity was examined in tumor lysates and transcriptome analysis carried out to identify pathways upregulated by FGFR inhibition. Anti-phosphotyrosine receptor antibody arrays (P-Tyr RTK) were also used to screen 4T1 tumors. Results The combination of dovitinib + NVP-BEZ235 causes tumor stasis and strong down-regulation of the FRS2/Erk and PI3K/Akt/mTOR signaling pathways. P-Tyr RTK arrays identified high levels of P-EGFR and P-ErbB2 in 4T1 tumors. Testing AEE788 in the tumor models revealed that the combination of dovitinib + AEE788 resulted in blockade of the PI3K/Akt/mTOR pathway, prolonged tumor stasis and in the 4T1 model, a significant decrease in lung metastasis. The results show that in vivo these breast cancer models become dependent upon co-activation of FGFR and ErbB receptors for PI3K pathway activity. Conclusions The work presented here shows that in the breast cancer models examined, the combination of dovitinib + NVP-BEZ235 or dovitinib + AEE788 results in strong inhibition of tumor growth and a block in metastatic spread. Only these combinations strongly down-regulate the FGFR/FRS2/Erk and PI3K/Akt/mTOR signaling pathways. The resultant decrease in mitosis and increase in apoptosis was consistently stronger in the dovitinib + AEE788 treatment-group, suggesting that targeting ErbB receptors has broader downstream effects compared to targeting only PI3K/mTOR. Considering that sub-classes of human breast tumors co-express ErbB receptors and FGFRs, these results have implications for targeted therapy.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1465-542X 1465-5411 1465-542X
DOI:	10.1186/bcr3379