Reference Detail

Ref Type Journal Article
PMID (25436981)
Authors Andrade-Vieira R, Goguen D, Bentley HA, Bowen CV, Marignani PA
Title Pre-clinical study of drug combinations that reduce breast cancer burden due to aberrant mTOR and metabolism promoted by LKB1 loss.
Journal Oncotarget
Vol 5
Issue 24
Date 2014 Dec 30
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
STK11 A205T mTOR Inhibitor
STK11 D207Gfs*59 mTOR Inhibitor
STK11 F157S mTOR Inhibitor
STK11 Y272H mTOR Inhibitor
STK11 E165* mTOR Inhibitor
STK11 G163D mTOR Inhibitor
STK11 E70* mTOR Inhibitor
STK11 T250P mTOR Inhibitor
STK11 inact mut mTOR Inhibitor
STK11 K78A mTOR Inhibitor
STK11 E138* mTOR Inhibitor
STK11 Q137* mTOR Inhibitor
STK11 F354L mTOR Inhibitor
STK11 K48fs mTOR Inhibitor
STK11 E223V mTOR Inhibitor
STK11 Q123* mTOR Inhibitor
STK11 E199* mTOR Inhibitor
STK11 L245R mTOR Inhibitor
STK11 S240* mTOR Inhibitor
STK11 D194Y mTOR Inhibitor
STK11 K62* mTOR Inhibitor
STK11 E120* mTOR Inhibitor
STK11 N181E mTOR Inhibitor
STK11 L67P mTOR Inhibitor
STK11 D194E mTOR Inhibitor
STK11 A218Sfs*42 mTOR Inhibitor
STK11 I35Lfs*127 mTOR Inhibitor
STK11 K44* mTOR Inhibitor
STK11 Y118* mTOR Inhibitor
STK11 P281Pfs*4 mTOR Inhibitor
STK11 Q170P mTOR Inhibitor
STK11 G61Afs*3 mTOR Inhibitor
STK11 Q159* mTOR Inhibitor
STK11 E65* mTOR Inhibitor
STK11 E223* mTOR Inhibitor
STK11 L285Q mTOR Inhibitor
STK11 G56Tfs*4 mTOR Inhibitor
STK11 E57fs mTOR Inhibitor
STK11 P281Rfs*6 mTOR Inhibitor
STK11 K62Sfs*100 mTOR Inhibitor
STK11 Q37* mTOR Inhibitor
STK11 E199K mTOR Inhibitor
STK11 Y60* mTOR Inhibitor
STK11 G171S mTOR Inhibitor
STK11 D277Y mTOR Inhibitor
STK11 L285Lfs*2 mTOR Inhibitor
STK11 Q220* mTOR Inhibitor
STK11 Q100* mTOR Inhibitor
STK11 L282Afs*3 mTOR Inhibitor
STK11 P281fs mTOR Inhibitor
STK11 P281L mTOR Inhibitor
STK11 K84* mTOR Inhibitor
STK11 D176Y mTOR Inhibitor
STK11 E33* mTOR Inhibitor
STK11 R304W mTOR Inhibitor
STK11 D176N mTOR Inhibitor
STK11 loss mTOR Inhibitor
STK11 Q214* mTOR Inhibitor
STK11 M136R mTOR Inhibitor
STK11 W308C mTOR Inhibitor
STK11 Q170* mTOR Inhibitor
STK11 S216F mTOR Inhibitor
STK11 D53Tfs*11 mTOR Inhibitor
STK11 E57Sfs*107 mTOR Inhibitor
STK11 K78I mTOR Inhibitor
STK11 I177N mTOR Inhibitor
STK11 E121* mTOR Inhibitor
STK11 H174R mTOR Inhibitor
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ERBB2 act mut STK11 loss breast cancer sensitive AZD8055 Preclinical Actionable In a preclinical study, AZD8055 inhibited tumor growth in a mouse model of spontaneous breast cancer harboring an ERBB2 (HER2) activating mutation and loss of STK11 (LKB1), which was enhanced by the addition of 2-DG (2-deoxyglucose) (PMID: 25436981). 25436981