Combinatorial targeting of FGF and ErbB receptors blocks growth and metastatic spread of breast cancer models.
BACKGROUND
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.
Amine
A
Issa
Jason W
JW
Gill
Marinus R
MR
Heideman
Ozgur
O
Sahin
Stefan
S
Wiemann
Julien H
JH
Dey
Nancy E
NE
Hynes
D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D051379:Mice; D058990:Molecular Targeted Therapy; D019869:Phosphatidylinositol 3-Kinases / Q000008:administration & dosage / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D011687:Purines / Q000008:administration & dosage; D011804:Quinolines / Q000008:administration & dosage; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D066246:ErbB Receptors; D007093:Imidazoles; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011687:Purines; D011804:Quinolines; D017468:Receptors, Fibroblast Growth Factor; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C489254:AEE 788; C531198:dactolisib