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Choline metabolism is an early predictor of EGFR-mediated survival in NSCLC

Favicchio, Rosy, Angelopoulos, Nicos, Brickute, Diana, Fortt, Robin, Twyman, Frazer, Giamas, Georgios, Lacal, Juan Carlos and Aboagye, Eric O. 2016. Choline metabolism is an early predictor of EGFR-mediated survival in NSCLC. Presented at: 107th Annual Meeting of the American Association for Cancer Research, New Orleans, LA, USA, 16-20 April 2016. Proceedings of the 107th Annual Meeting of the American Association for Cancer Research. , vol. 14. Philadelphia, PA, USA: American Association for Cancer Research, p. 4235. 10.1158/1538-7445.AM2016-4235

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Oncogenic signalling and metabolic reprograming are hallmarks of tumour progression, yet little is known about the regulatory elements that coordinate their interface. Aberrant choline and phospholipid metabolism are strongly correlated to malignant progression in NSCLC and provide the essential components required by both hallmarks and yet mechanistic links to either remain scarce. Choline kinase alpha (ChoKα) regulates the conversion of choline to phosphocholine and although its regulatory cascade has not been described, it is thought to act in conjuction with EGFR. We used an integrated systems approach and queried whether pharmacoproteomic pathway mapping could identify regulators of the cholinic phenotype. Proteomic and phosphoproteomic Stable isotope labelling by amino acids in cell culture (SILAC) analysis was used to describe the interactome following ChoKα or EGFR inhibition. Bioinformatic analysis was used to identify the significant (Significance-B test) subset of targets for each condition. These subsets were clustered according to GeneOntology, Reactome and KEGG databases and the resulting maps identifed the potential regulators of choline metabolism. Choline uptake, phosphorylation and efflux were further evaluated in vitro in response to erlotinib, cisplatin, pemetrexed and paclitaxel using radio-labelled Choline analogues. Derived metabolites were characterised using radio-HPLC. Uptake was further characterised under hypoxic and nutrient deficient conditions. In vivo, [18F]-D4-Choline PET dynamic imaging was performed following treatment. Pharmacoproteomic analysis revealed a 40% overlap between ChoKα and EGFR inhibition providing direct evidence of the pathways and targets involved in, mostly, biosynthesis. Rapid modulation of the cholinic phenotype was directly dependent on ChoKα activity. Intracellular uptake was induced by nutrient deprivation, hypoxia and reversed through second messenger signalling or growth factor stimulation. Choline uptake within 3 hours of treatment correlated to survival at 72 hours. In vivo, [18F]-D4-Choline tracer kinetics were diagnostic of choline kinase expression and sensitive to treatment. Significant correspondence between ChoKα and EGFR inhibition provided mechanistic evidence that ChoKα and lipid metabolism are effectors of the EGFR signalling cascade in NSCLC. Choline can act as a sensor by synchronizing the survival response via metabolic and signalling reprograming and is thus an early predictor of therapeutic efficiency in vitro and in vivo.

Item Type: Conference or Workshop Item (Paper)
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: American Association for Cancer Research
ISSN: 0008-5472
Date of Acceptance: 20 February 2016
Last Modified: 31 Jul 2020 09:46

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