title: Pre-clinical study of drug combinations that reduce breast cancer burden due to aberrant mTOR and metabolism promoted by LKB1 loss.
abstract: Cancer therapies that simultaneously target activated mammalian target of rapamycin (mTOR) and cell metabolism are urgently needed. The goal of our study was to identify therapies that effectively inhibited both mTOR activity and cancer cell metabolism in primary tumors in vivo. Using our mouse model of spontaneous breast cancer promoted by loss of LKB1 expression in an ErbB2 activated model; referred to as LKB1-/-NIC mice, we evaluated the effect of novel therapies in vivo on primary tumors. Treatment of LKB1-/-NIC mice with AZD8055 and 2-DG mono-therapies significantly reduced mammary gland tumorigenesis by inhibiting mTOR pathways and glycolytic metabolism; however simultaneous inhibition of these pathways with AZD8055/2-DG combination was significantly more effective at reducing tumor volume and burden. At the molecular level, combination treatment inhibited mTORC1/mTORC2 activity, selectively inhibited mitochondria function and blocked MAPK pro-survival signaling responsible for the ERK-p90RSK feedback loop. Our findings suggest that loss of LKB1 expression be considered a marker for metabolic dysfunction given its role in regulating AMPK and mTOR function. Finally, the outcome of our pre-clinical study confirms therapies that simultaneously target mTORC1/mTORC2 and glycolytic metabolism in cancer produce the best therapeutic outcome for the treatment of patients harboring metabolically active HER2 positive breast cancers.
authors.affiliation: Department of Biochemistry and Molecular Biology, Dalhousie University, Faculty of Medicine, Halifax, Nova Scotia Canada.
authors.forename: Rafaela
authors.initials: R
authors.lastname: Andrade-Vieira
authors.affiliation: Department of Biochemistry and Molecular Biology, Dalhousie University, Faculty of Medicine, Halifax, Nova Scotia Canada.
authors.forename: Donna
authors.initials: D
authors.lastname: Goguen
authors.affiliation: Department of Biochemistry and Molecular Biology, Dalhousie University, Faculty of Medicine, Halifax, Nova Scotia Canada.
authors.forename: Heidi A
authors.initials: HA
authors.lastname: Bentley
authors.affiliation: Department of Radiology, Halifax, Nova Scotia Canada.
authors.forename: Chris V
authors.initials: CV
authors.lastname: Bowen
authors.affiliation: Department of Biochemistry and Molecular Biology, Dalhousie University, Faculty of Medicine, Halifax, Nova Scotia Canada.
authors.forename: Paola A
authors.initials: PA
authors.lastname: Marignani
mesh_terms: D055372:AMP-Activated Protein Kinases; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D003847:Deoxyglucose / Q000008:administration & dosage / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D006019:Glycolysis / Q000187:drug effects; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D007093:Imidazoles; D009025:Morpholines; D011804:Quinolines; C546624:(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol; D003847:Deoxyglucose; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C531198:dactolisib