Lei Xue1,2, Fengju Chen3, Fei Yue2, Laura Camacho2, Sushma Kothapalli2, Guanyun Wei1, Shixia Huang4,3, Qianxing Mo3, Fei Ma1, Yi Li5, Sao Jiralerspong6,7. 1. Laboratory for Comparative Genomics and Bioinformatics, College of Life Science, Nanjing Normal University, 1 Wenyuan Road, Nanjing, 210046, Jiangsu, China. 2. Lester & Sue Smith Breast Center, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA. 3. Dan L Duncan Cancer Center, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA. 4. Department of Molecular and Cellular Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA. 5. Lester & Sue Smith Breast Center, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA. liyi@bcm.edu. 6. Lester & Sue Smith Breast Center, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA. sjiral@arizona.edu. 7. Section of Breast Medical Oncology, Division of Hematology and Oncology, University of Arizona Cancer Center, 1515 N. Campbell Ave, Tucson, AZ, 85724, USA. sjiral@arizona.edu.
Abstract
PURPOSE: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with poor survival outcomes. Metformin has been shown to have antitumor effects by lowering serum levels of the mitogen insulin and having pleiotropic effects on cancer cell signaling pathways. BMS-754807 is a potent and reversible inhibitor of both insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor (IR). Both drugs have been reported to have some efficacy in TNBC. However, it is unclear whether the combination of the two drugs is more effective than single drug treatment in TNBC. METHODS: We treated a panel of TNBC cell lines with metformin and BMS-754807 alone and in combination and tested cell viability using MTS assays. We used the CompuSyn software to analyze for additivity, synergism, or antagonism. We also examined the molecular mechanism by performing reverse phase protein assay (RPPA) to detect the candidate pathways altered by single drugs and the drug combination and used Western blotting to verify and expand the findings. RESULTS: The combination of metformin and BMS-754807 showed synergy in 11 out of 13 TNBC cell lines tested (85%). RPPA analysis detected significant alterations by the drug combination of multiple proteins known to regulate cell cycle and tumor growth. In particular, the drug combination significantly increased levels of total and phosphorylated forms of the cell cycle inhibitor p27Kip1 and decreased the level of the p27Kip1 E3 ligase SCFSkp2. CONCLUSIONS: We conclude that the combination of metformin and BMS-754807 is more effective than either drug alone in inhibiting cell proliferation in the majority of TNBC cell lines, and that one important mechanism may be suppression of SCFSkp2 and subsequent stabilization of the cell cycle inhibitor p27Kip1. This combination treatment may represent an effective targeted therapy for a significant subset of TNBC cases and should be further evaluated.
PURPOSE: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with poor survival outcomes. Metformin has been shown to have antitumor effects by lowering serum levels of the mitogen insulin and having pleiotropic effects on cancer cell signaling pathways. BMS-754807 is a potent and reversible inhibitor of both insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor (IR). Both drugs have been reported to have some efficacy in TNBC. However, it is unclear whether the combination of the two drugs is more effective than single drug treatment in TNBC. METHODS: We treated a panel of TNBC cell lines with metformin and BMS-754807 alone and in combination and tested cell viability using MTS assays. We used the CompuSyn software to analyze for additivity, synergism, or antagonism. We also examined the molecular mechanism by performing reverse phase protein assay (RPPA) to detect the candidate pathways altered by single drugs and the drug combination and used Western blotting to verify and expand the findings. RESULTS: The combination of metformin and BMS-754807 showed synergy in 11 out of 13 TNBC cell lines tested (85%). RPPA analysis detected significant alterations by the drug combination of multiple proteins known to regulate cell cycle and tumor growth. In particular, the drug combination significantly increased levels of total and phosphorylated forms of the cell cycle inhibitor p27Kip1 and decreased the level of the p27Kip1 E3 ligase SCFSkp2. CONCLUSIONS: We conclude that the combination of metformin and BMS-754807 is more effective than either drug alone in inhibiting cell proliferation in the majority of TNBC cell lines, and that one important mechanism may be suppression of SCFSkp2 and subsequent stabilization of the cell cycle inhibitor p27Kip1. This combination treatment may represent an effective targeted therapy for a significant subset of TNBC cases and should be further evaluated.
Entities:
Keywords:
BMS-754807; IGF-1R inhibitor; Insulin receptor inhibitor; Metformin; Triple-negative breast cancer (TNBC)
Authors: Kimberly D Miller; Leticia Nogueira; Angela B Mariotto; Julia H Rowland; K Robin Yabroff; Catherine M Alfano; Ahmedin Jemal; Joan L Kramer; Rebecca L Siegel Journal: CA Cancer J Clin Date: 2019-06-11 Impact factor: 508.702
Authors: V Papa; B Gliozzo; G M Clark; W L McGuire; D Moore; Y Fujita-Yamaguchi; R Vigneri; I D Goldfine; V Pezzino Journal: Cancer Res Date: 1993-08-15 Impact factor: 12.701