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Non-small cell lung cancer (NSCLC) is one of the deadliest cancers worldwide, with patients presenting an overall 5-year survival lower than 15%. NSCLC is characterized by a multitude of tumor-promoting genetic alterations, such as mutations in KRAS, EGFR and TP53 genes. The high heterogeneity and plasticity of lung cancers is one of the main reasons for the failure of current treatment strategies. Importantly, genomic amplification of RICTOR frequently occurs in lung cancer. RICTOR is the defining component of mTOR complex 2 (mTORC2). Moreover, RICTOR-dependent activation of mTORC2 is essential to support lung cancer cell survival and tumor growth in vivo. Despite high therapeutic potential, directly targeting mTORC2 activity in patients remains challenging. Therefore, targeting mTORC2-dependent liabilities may represent a better option for the development of anticancer treatments. Preliminary work from our lab and results from the literature have positioned mTORC2 signaling at the crossroad between translation and metabolism. Hence, deciphering the mechanisms linking mTORC2-dependent translation to the acquisition of specific metabolic liabilities will highlight new therapeutic strategies for the treatment of lung cancer. In this study, I focused on understanding the molecular mechanisms that sustain the rewiring of cancer cell metabolism in the clinically relevant context of RICTOR-overexpressing (RICTOR OE) lung cancer. Using several models, I first evidenced an active role for RICTOR/mTORC2 in the regulation of cancer associated mRNA translation. Preliminary data from the lab indicated that RICTOR silencing in human lung cancer cells was associated with a negative enrichment of hypoxia signatures. Therefore, I first assessed the expression of the different hypoxia-inducible factors (HIF-1α, HIF-2α and HIF-1β) in RICTOR-depleted lung cancer cells. Strikingly, I found that expression of the transcription factor HIF-1β was significantly and consistently decreased upon RICTOR silencing. Importantly, RICTOR-dependent modulation of HIF-1β expression occurred at protein level and was observed in multiple cancer cell lines, highlighting HIF-1β as a potential RICTOR-dependent translational target in lung cancer. Using pharmacological and genetic inhibition of mTOR signaling (RICTOR, RAPTOR and SIN1 siRNAs; mTOR, AKT and PKC inhibitors) I further showed that RICTOR controlled HIF-1β expression through an mTOR-PKC signaling axis, independently of AKT activity. Finally, I demonstrated that HIF-1β levels correlated with mTORC2 activation in vivo, in a mouse model of RICTOR OE. Taken together, my results highlight HIF-1β as a clinically relevant target and support targeting of hypoxia-mediated metabolism as a potential therapeutic approach for the treatment of lung cancer.

lung cancer --- mRNA translation --- metabolism --- mTORC2 --- RICTOR --- HIF1beta --- HIF-1β --- signaling pathways --- Sciences du vivant > Biochimie, biophysique & biologie moléculaire

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Despite the efficiency of current cancer treatments, cancer is still a deadly disease for too many. In 2008, 7.6 million people died of cancer; with the current development, it is estimated that the annual cancer death number will grow to 13 million by 2030. There is clearly a need for not only more research but also more innovative and out of the mainstream scientific ideas to discover and develop even better cancer treatments. This book presents the collective works published in the recent Special Issue entitled “Killing Cancer: Discovery and Selection of New Target Molecules”. These articles comprise a selection of studies, ideas, and opinions that aim to facilitate knowledge, thoughts, and discussion about which biological and molecular mechanisms in cancer we should target and how we should target them.

Research & information: general --- Biology, life sciences --- ferlin --- myoferlin --- dysferlin --- otoferlin --- C2 domain --- plasma membrane --- sulconazole --- NF-κB --- IL-8 --- mammosphere --- breast cancer stem cells --- AF1Q --- MLLT11 --- WNT --- STAT --- esophageal cancer --- prognosis --- mTORC1 --- mTORC2 --- metabolism --- rapalogs --- mTOR inhibitors --- cancer metabolism --- mTOR in immunotherapy --- nutrient metabolism --- kinase inhibitors --- mTOR signaling --- MAPK kinase --- ERK1 --- ERK2 --- CD domain --- Rolled --- SCH772984 --- VRT-11E --- sevenmaker --- cancer therapy --- EMT --- lysosome --- lysosome-mediated invasion --- MZF1 --- phosphorylation --- PAK4 --- SUMOylation --- transcription factor --- zinc finger --- glucocorticoids --- 3D growth --- nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) --- epithelial-mesenchymal transition --- anoikis --- proliferation --- targeted cancer therapy --- disulfiram --- NPL4 --- replication stress --- DNA damage --- BRCA1 --- BRCA2 --- ATR pathway --- PDAC --- TCIRG1 --- ATP6V0a3 --- invasion --- migration --- matrix degradation --- pH-regulation --- autophagy --- multidrug resistance in cancer --- drug efflux pumps --- ATP-binding cassette transporter --- breast cancer resistance protein (BCRP) --- ABCG2 --- pyrazolo-pyrimidine derivative --- SCO-201 --- colorectal cancer --- immunotherapy --- inflammation --- microsatellite instability --- oncofetal chondroitin sulfate --- chondroitin sulfate --- cancer --- solid tumors --- target --- pediatric cancer --- VAR2 --- dexamethasone --- thyroid cancer --- microgravity --- space environment --- ferlin --- myoferlin --- dysferlin --- otoferlin --- C2 domain --- plasma membrane --- sulconazole --- NF-κB --- IL-8 --- mammosphere --- breast cancer stem cells --- AF1Q --- MLLT11 --- WNT --- STAT --- esophageal cancer --- prognosis --- mTORC1 --- mTORC2 --- metabolism --- rapalogs --- mTOR inhibitors --- cancer metabolism --- mTOR in immunotherapy --- nutrient metabolism --- kinase inhibitors --- mTOR signaling --- MAPK kinase --- ERK1 --- ERK2 --- CD domain --- Rolled --- SCH772984 --- VRT-11E --- sevenmaker --- cancer therapy --- EMT --- lysosome --- lysosome-mediated invasion --- MZF1 --- phosphorylation --- PAK4 --- SUMOylation --- transcription factor --- zinc finger --- glucocorticoids --- 3D growth --- nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) --- epithelial-mesenchymal transition --- anoikis --- proliferation --- targeted cancer therapy --- disulfiram --- NPL4 --- replication stress --- DNA damage --- BRCA1 --- BRCA2 --- ATR pathway --- PDAC --- TCIRG1 --- ATP6V0a3 --- invasion --- migration --- matrix degradation --- pH-regulation --- autophagy --- multidrug resistance in cancer --- drug efflux pumps --- ATP-binding cassette transporter --- breast cancer resistance protein (BCRP) --- ABCG2 --- pyrazolo-pyrimidine derivative --- SCO-201 --- colorectal cancer --- immunotherapy --- inflammation --- microsatellite instability --- oncofetal chondroitin sulfate --- chondroitin sulfate --- cancer --- solid tumors --- target --- pediatric cancer --- VAR2 --- dexamethasone --- thyroid cancer --- microgravity --- space environment