title: Flavopiridol synergizes with sorafenib to induce cytotoxicity and potentiate antitumorigenic activity in EGFR/HER-2 and mutant RAS/RAF breast cancer model systems.
abstract: Oncogenic receptor tyrosine kinase (RTK) signaling through the Ras-Raf-Mek-Erk (Ras-MAPK) pathway is implicated in a wide array of carcinomas, including those of the breast. The cyclin-dependent kinases (CDKs) are implicated in regulating proliferative and survival signaling downstream of this pathway. Here, we show that CDK inhibitors exhibit an order of magnitude greater cytotoxic potency than a suite of inhibitors targeting RTK and Ras-MAPK signaling in cell lines representative of clinically recognized breast cancer (BC) subtypes. Drug combination studies show that the pan-CDK inhibitor, flavopiridol (FPD), synergistically potentiated cytotoxicity induced by the Raf inhibitor, sorafenib (SFN). This synergy was most pronounced at sub-EC50 SFN concentrations in MDA-MB-231 (KRAS-G13D and BRAF-G464V mutations), MDA-MB-468 [epidermal growth factor receptor (EGFR) overexpression], and SKBR3 [ErbB2/EGFR2 (HER-2) overexpression] cells but not in hormone-dependent MCF-7 and T47D cells. Potentiation of SFN cytotoxicity by FPD correlated with enhanced apoptosis, suppression of retinoblastoma (Rb) signaling, and reduced Mcl-1 expression. SFN and FPD were also tested in an MDA-MB-231 mammary fat pad engraftment model of tumorigenesis. Mice treated with both drugs exhibited reduced primary tumor growth rates and metastatic tumor load in the lungs compared to treatment with either drug alone, and this correlated with greater reductions in Rb signaling and Mcl-1 expression in resected tumors. These findings support the development of CDK and Raf co-targeting strategies in EGFR/HER-2-overexpressing or RAS/RAF mutant BCs.
authors.affiliation: Division of Cancer Biology and Genetics, Queen's Cancer Research Institute, Queen's University, Kingston, Ontario, Canada.
authors.forename: Teddy S
authors.initials: TS
authors.lastname: Nagaria
authors.forename: Julia L
authors.initials: JL
authors.lastname: Williams
authors.forename: Charles
authors.initials: C
authors.lastname: Leduc
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Squire
authors.forename: Peter A
authors.initials: PA
authors.lastname: Greer
authors.forename: Waheed
authors.initials: W
authors.lastname: Sangrar
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004357:Drug Synergism; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D005419:Flavonoids / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009154:Mutation; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D000077157:Sorafenib; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D048490:raf Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D018844:Cyclin-Dependent Kinases; D066246:ErbB Receptors; D005419:Flavonoids; D009536:Niacinamide; D010671:Phenylurea Compounds; D010880:Piperidines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000077157:Sorafenib; D048490:raf Kinases; D018631:ras Proteins; C077990:alvocidib; C512478:EGFR protein, human
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