Amplification of fibroblast growth factor receptor-1 in breast cancer and the effects of brivanib alaninate.
Fibroblast growth factor receptor-1 (FGFR-1) is amplified in 10% of human breast cancers. The goal of this study was to test the correlation between FGFR-1 amplification and expression and sensitivity to brivanib, an FGFR-1 small molecule inhibitor, in breast cancer cell lines in vitro. Using CGH array and gene expression profiling, FGFR-1 DNA copy number, mRNA, and protein expression were measured in 21 cell lines and correlated with growth inhibition by brivanib. We examined FGFR-1 autophosphorylation and kinase activity, as well as phosphorylation of downstream signaling molecules in response to bFGF and brivanib exposure. CAMA, MDA-MB-361, and HCC38 cells had FGFR-1 amplification and protein overexpression. Brivanib GI(50) values were significantly lower in the gene amplified (15.17 μM, n = 3) compared to normal copy number (69.09 μM, n = 11) or FGFR-1 deleted (76.14 μM, n = 7) cells (P = 0.0107). Among nonamplified cells, there was no correlation between FGFR-1 mRNA or protein expression levels and brivanib sensitivity. Two of three FGFR-1 amplified cells were sensitive to bFGF-induced growth stimulation, which was blocked by brivanib. In cells with amplified FGFR-1, brivanib decreased receptor autophosphorylation, inhibited bFGF-induced tyrosine kinase activity, and reduced phosphorylation of ERK and AKT. Breast cancer cell lines with FGFR-1 gene amplification and protein overexpression are more sensitive to growth inhibition by brivanib than nonamplified cells. These findings suggest that FGFR-1 amplification or protein overexpression in breast cancers may be an indicator for brivanib treatment, where it may have direct anti-proliferative effects in addition to its' anti-angiogenic effects.
Shiang
Christine Y
CY
Department of Breast Medical Oncology, Unit 1354, The University of Texas M. D. Anderson Cancer Center, P.O. Box 301439, Houston, TX 77230-1439, USA. cshiang@mdanderson.org
Qi
Yuan
Y
Wang
Bailiang
B
Lazar
Vladimir
V
Wang
Jing
J
Fraser Symmans
W
W
Hortobagyi
Gabriel N
GN
Andre
Fabrice
F
Pusztai
Lajos
L
D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D055028:Comparative Genomic Hybridization; D004305:Dose-Response Relationship, Drug; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005784:Gene Amplification; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020128:Inhibitory Concentration 50; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014227:Triazines / Q000494:pharmacology*
D000970:Antineoplastic Agents; D012333:RNA, Messenger; D014227:Triazines; D016222:Fibroblast Growth Factor 2; C509922:brivanib; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000409:Alanine