Pre-clinical study of drug combinations that reduce breast cancer burden due to aberrant mTOR and metabolism promoted by LKB1 loss

Andrade-Vieira, Rafaela; Goguen, Donna; Bentley, Heidi A.; Bowen, Chris V.; Marignani, Paola A.

doi:10.18632/oncotarget.2818

Cited by 23 publications

(29 citation statements)

References 51 publications

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“…We show the combination of MLN0128 and phenformin lead to a severe reduction of cellular ATP and eventual metabolic crisis likely due to a dual inhibition both glycolysis and OXPHOS in LKB1-deficient tumors. Our data agree with a recent report that reduced breast tumor growth in Lkb1−/− NIC mice using the mTOR inhibitor AZ8055 in combination with an inhibitor of glycolysis, 2-deoxyglucose(7,37). 18FFDG PET guided pre-clinical studies on KL luc and K luc mice enabled us to examine glucose metabolism in lung tumors in real time as well as validate 18F-FDG as a biomarker for clinical evaluation of phenformin and MLN0128.…”

Section: Discussionsupporting

confidence: 93%

Heightening Energetic Stress Selectively Targets LKB1-Deficient Non–Small Cell Lung Cancers

et al. 2015

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Inactivation of the LKB1 tumor suppressor is a frequent event in non-small cell lung carcinoma (NSCLC) leading to the activation of mammalian target of rapamycin complex 1 (mTORC1) and sensitivity to the metabolic stress inducer phenformin. In this study, we explored the combinatorial use of phenformin with the mTOR catalytic kinase inhibitor MLN0128 as a treatment strategy for NSCLC bearing co-mutations in the LKB1 and KRAS genes. NSCLC is a genetically and pathologically heterogeneous disease, giving rise to lung tumors of varying histologies that include adenocarcinomas (ADCs) and squamous cell carcinomas (SCCs). We demonstrate that phenformin in combination with MLN0128 induced a significant therapeutic response in KRAS/LKB1 mutant human cell lines and genetically engineered mouse models of NSCLC that develop both ADCs and SCCs. Specifically, we found that KRAS/LKB1 mutant lung ADCs responded strongly to phenformin + MLN0128 treatment, but the response of SCCs to single or combined treatment with MLN0128 was more attenuated due to acquired resistance to mTOR inhibition through modulation of the AKT-GSK signaling axis. Combinatorial use of the mTOR inhibitor and AKT inhibitor MK2206 robustly inhibited the growth and viability of squamous lung tumors thus providing an effective strategy to overcome resistance. Taken together, our findings define new personalized therapeutic strategies that may be rapidly translated into clinical use for the treatment of KRAS/LKB1 mutant adenocarcinomas and squamous cell tumors.

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Section: Discussionsupporting

confidence: 93%

Heightening Energetic Stress Selectively Targets LKB1-Deficient Non–Small Cell Lung Cancers

et al. 2015

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“…Oct4, Nanog, Sox2 upregulation upon LKB1-depletion was validated using spontaneous breast tumors from Lkb1 −/− /NIC mice and Lkb1 lox/lox mice. 7 Indeed, immunoblot analysis of Lkb1 −/− /NIC tumors exhibited increased expression of Oct4, Nanog and Sox2 whereas tumors from LKB1 lox/lox mice showed extremely low expression of these iPSC inducers (Figure 2f). Immunohistochemical analysis of Lkb1 −/− /NIC tumors exhibited significantly more tumor cells showing higher expression of Oct4, Nanog and Sox2.…”

Section: Resultsmentioning

confidence: 96%

Activation of tumor suppressor LKB1 by honokiol abrogates cancer stem-like phenotype in breast cancer via inhibition of oncogenic Stat3

et al. 2017

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Tumor suppressor and upstream master kinase Liver kinase B1 (LKB1) plays a significant role in suppressing cancer growth and metastatic progression. We show that low-LKB1 expression significantly correlates with poor survival outcome in breast cancer. In line with this observation, loss-of-LKB1 rendered breast cancer cells highly migratory and invasive, attaining cancer stem cell-like phenotype. Accordingly, LKB1-null breast cancer cells exhibited an increased ability to form mammospheres and elevated expression of pluripotency-factors (Oct4, Nanog and Sox2), properties also observed in spontaneous tumors in Lkb1−/− mice. Conversely, LKB1-overexpression in LKB1-null cells abrogated invasion, migration and mammosphere-formation. Honokiol (HNK), a bioactive molecule from Magnolia grandiflora increased LKB1 expression, inhibited individual cell-motility and abrogated the stem-like phenotype of breast cancer cells by reducing the formation of mammosphere, expression of pluripotency-factors and aldehyde dehydrogenase activity. LKB1, and its substrate, AMP-dependent protein kinase (AMPK) are important for HNK-mediated inhibition of pluripotency factors since LKB1-silencing and AMPK-inhibition abrogated, while LKB1-overexpression and AMPK-activation potentiated HNK’s effects. Mechanistic studies showed that HNK inhibited Stat3-phosphorylation/activation in an LKB1-dependent manner, preventing its recruitment to canonical binding-sites in the promoters of Nanog, Oct4 and Sox2. Thus, inhibition of the coactivation-function of Stat3 resulted in suppression of expression of pluripotency factors. Further, we showed that HNK inhibited breast tumorigenesis in mice in an LKB1-dependent manner. Molecular analyses of HNK-treated xenografts corroborated our in vitro mechanistic findings. Collectively, these results present the first in vitro and in vivo evidence to support crosstalk between LKB1, Stat3 and pluripotency factors in breast cancer and effective anticancer modulation of this axis with HNK treatment.

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“…During the past decades, LKB1 has been well-described as a tumor suppressor, since its loss-of-function mutation is commonly detected and believed to directly induce the oncogenesis in a wide range of malignancies [42]. Knockout mice models have been extensively applied to study the molecular basis of LKB1 associated carcinogenesis.…”

Section: Functions Of Ampk Signaling Components In Tumorigenesismentioning

confidence: 99%

Functional characterization of AMP-activated protein kinase signaling in tumorigenesis

Cheng

Zhang

et al. 2016

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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AMP-activated protein kinase (AMPK) is a ubiquitously expressed metabolic sensor among various species. Specifically, cellular AMPK is phosphorylated and activated under certain stressful conditions, such as energy deprivation, in turn to activate diversified downstream substrates to modulate the adaptive changes and maintain metabolic homeostasis. Recently, emerging evidences have implicated the potential roles of AMPK signaling in tumor initiation and progression. Nevertheless, a comprehensive description on such topic is still in scarcity, especially in combination of its biochemical features with mouse modeling results to elucidate the physiological role of AMPK signaling in tumorigenesis. Hence, we performed this thorough review by summarizing the tumorigenic role of each component along the AMPK signaling, comprising of both its upstream and downstream effectors. Moreover, their functional interplay with the AMPK heterotrimer and exclusive efficacies in carcinogenesis were chiefly explained among genetically altered mice models. Importantly, the pharmaceutical investigations of AMPK relevant medications have also been highlighted. In summary, in this review, we not only elucidate the potential functions of AMPK signaling pathway in governing tumorigenesis, but also potentiate the future targeted strategy aiming for better treatment of aberrant metabolism-associated diseases, including cancer.

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Pre-clinical study of drug combinations that reduce breast cancer burden due to aberrant mTOR and metabolism promoted by LKB1 loss

Cited by 23 publications

References 51 publications

Heightening Energetic Stress Selectively Targets LKB1-Deficient Non–Small Cell Lung Cancers

Heightening Energetic Stress Selectively Targets LKB1-Deficient Non–Small Cell Lung Cancers

Activation of tumor suppressor LKB1 by honokiol abrogates cancer stem-like phenotype in breast cancer via inhibition of oncogenic Stat3

Functional characterization of AMP-activated protein kinase signaling in tumorigenesis

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