title: Multiple metabolic alterations exist in mutant PI3K cancers, but only glucose is essential as a nutrient source.
abstract: Targeting tumour metabolism is becoming a major new area of pharmaceutical endeavour. Consequently, a systematic search to define whether there are specific energy source dependencies in tumours, and how these might be dictated by upstream driving genetic mutations, is required. The PI3K-AKT-mTOR signalling pathway has a seminal role in regulating diverse cellular processes including cell proliferation and survival, but has also been associated with metabolic dysregulation. In this study, we sought to define how mutations within PI3KCA may affect the metabolic dependency of a cancer cell, using precisely engineered isogenic cell lines. Studies revealed gene expression signatures in PIK3CA mutant cells indicative of a consistent up-regulation of glycolysis. Interestingly, the genes up- and down-regulated varied between isogenic models suggesting that the primary node of regulation is not the same between models. Additional gene expression changes were also observed, suggesting that metabolic pathways other than glycolysis, such as glutaminolysis, were also affected. Nutrient dependency studies revealed that growth of PIK3CA mutant cells is highly dependent on glucose, whereas glutamine dependency is independent of PIK3CA status. In addition, the glucose dependency exhibited by PIK3CA mutant cells could not be overridden by supplementation with other nutrients. This specific dependence on glucose for growth was further illustrated by studies evaluating the effects of targeted disruption of the glycolytic pathway using siRNA and was also found to be present across a wider panel of cancer cell lines harbouring endogenous PIK3CA mutations. In conclusion, we have found that PIK3CA mutations lead to a shift towards a highly glycolytic phenotype, and that despite suggestions that cancer cells are adept at utilising alternative nutrient sources, PIK3CA mutant cells are not able to compensate for glucose withdrawal. Understanding the metabolic dependencies of PIK3CA mutant cancers will provide critical information for the design of effective therapies and tumour visualisation strategies.
authors.affiliation: Horizon Discovery Ltd, Cambridge, Cambridgeshire, United Kingdom. rebecca.foster@horizondiscovery.com
authors.forename: Rebecca
authors.initials: R
authors.lastname: Foster
authors.forename: Sue
authors.initials: S
authors.lastname: Griffin
authors.forename: Suzanne
authors.initials: S
authors.lastname: Grooby
authors.forename: Ruth
authors.initials: R
authors.lastname: Feltell
authors.forename: Cindy
authors.initials: C
authors.lastname: Christopherson
authors.forename: Monica
authors.initials: M
authors.lastname: Chang
authors.forename: John
authors.initials: J
authors.lastname: Sninsky
authors.forename: Shirley
authors.initials: S
authors.lastname: Kwok
authors.forename: Chris
authors.initials: C
authors.lastname: Torrance
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D058534:Class I Phosphatidylinositol 3-Kinases; D004789:Enzyme Activation / Q000187:drug effects; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018390:Gene Targeting; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D005973:Glutamine / Q000378:metabolism / Q000494:pharmacology; D006019:Glycolysis / Q000187:drug effects / Q000235:genetics; D006801:Humans; D055442:Metabolome / Q000187:drug effects / Q000235:genetics; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D050505:Mutant Proteins; D005973:Glutamine; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D005947:Glucose