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.
Highlights
The metabolic branch of mammalian target of rapamycin signaling is primarily dependent on the energy sensing 5’ AMP-activated protein kinase (AMPK) and is under-utilized as a strategy to target aberrant mTOR signaling
We found that inhibition of mTOR with AZD8055, a novel ATP-competitive inhibitor of mTOR that inhibits both mTORC1 and mTORC2 [10], inhibited mTOR signaling and expression of glycolytic enzymes, lactate dehydrogenase (LDH) and pyruvate dehydrogenase (PDH), in primary breast cancer cells isolated from LKB1/-NIC mice [9]
To determine whether loss of LKB1 expression is responsible for enhanced breast cancer cell metabolism, we analyzed the presence of metabolites in whole LKB1-/-NIC mammary tumors compared to tumors harvested from NIC control mice and from wild-type (WT) mammary glands by NMR analysis (Chenomx Inc.) (Fig.1)
Summary
The metabolic branch of mammalian target of rapamycin (mTOR) signaling is primarily dependent on the energy sensing 5’ AMP-activated protein kinase (AMPK) and is under-utilized as a strategy to target aberrant mTOR signaling. The main activator of AMPK is the serine-threonine tumor suppressor kinase LKB1, which is responsible for phosphorylating AMPK on Thr172, leading to the activation of the energy sensor [1, 2]. Both somatic and sporadic mutations have been identified in LKB1 and are responsible for numerous malignancies [3]. Current treatment strategies are at various stages of clinical trial, NVP-BEZ235, PF-04691502 and BKM120 [4,5,6] These new compounds are promising there may be limitations as these drugs are highly dependent on tumor sub-type, are specific to particular genetic alterations, and may lead to the activation of www.impactjournals.com/oncotarget negative feedback loops that acerbate resistance or recurrence. By exclusively targeting activating mutations in the PI3K/AKT branch of mTOR signaling, it stands to reason that if these same cancers express mutation in LKB1 or express isoforms of the pseudokinase STRADα that render LKB1 catalytically deficient [7], the tumors may initially regress in response to treatment, because AMPK activity is deregulated and the mTORC1MAPK feedback loop is activated [8], the cancer will invariably return and/or be resistant to future treatments
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