Understanding Tumour Metabolic Reprogramming with Metabolomics

Abstract

Although cancer is well recognised as a genetic disease, there is an emerging awareness that many of these genetic mutations promote an established hallmark of tumour cells – metabolic reprogramming. And while the connection between oncogenic signalling and the metabolic reprogramming of tumour cells (in hindsight) is highly intuitive, how to expand on this knowledge and capitalise on it for therapeutic gain is yet to be fully actualised. An emerging opportunity to expand this possibility involves taking advantage of the fact that diverse genetic alterations in tumour cells converge to the shared features of metabolic reprogramming. Therefore, these features could offer a common means to target the tumour irrespective of the mutational status. However, in all likelihood, the most selective and efficacious treatments will emerge from combining data to specifically define the genetic and metabolic features of a tumour with modern genomic and metabolomic technologies. Conceptually, genotyping and metabotyping can be combined in an effort to define efficacious first line dual‐targeted combinations. Although there are many practical considerations and challenges to achieve this end, the premise will be described through a number of preclinical examples that begin to offer an illustration of this possibility.

Key Concepts:

  • Oncogenes and tumour suppressors directly regulate metabolic reprogramming.

  • Metabolic reprogramming supports tumour energetics, biosynthesis and survival.

  • Metabolic targets present viable options for therapeutic development.

  • Global metabolite profiling provides knowledge into tumour signalling pathway dysregulation.

  • Metabolic reprogramming contributes to therapeutic resistance/sensitivity.

  • Understanding malignant cell metabolism affords greater insight into optimal drug combination strategies.

  • Metabolomics combined with genotyping offers an opportunity to advance personalised cancer medicine.

Keywords: metabolic reprogramming; metabolomics; metabotyping; combination therapy; metabolic targets; oncogenes

Figure 1.

Metabolic reprogramming in tumours offers a common feature by which to consider targeting. (a) Oncogenic activators such as KRas, Myc, PI3K, P53, and B‐rapidly accelerated fibrosarcoma are connected within a complex signalling web that, among many other functions, ultimately distils into a common feature of metabolic reprogramming. This is classically centred on glucose and glutamine metabolism, with other key anabolic nodes involving lipid, amino acid and nucleotide metabolism also gaining appreciation. However, there are many emerging metabolic nodes that suggest that there may in fact be a greater diversity of metabolic targets than one might have anticipated. (b) Cancers can either have unique oncogenic genotypes and share common phenotypic and histological characteristics (genotype‐independent phenotypes) or can possess the same driver mutations but result in different types of malignancies. Metabolic reprogramming is a common feature of either case, and in this way, may serve as a means to simplify genomic complexities. Thus, targeting metabolic reprogramming in combination with other targeted therapies or in the face of resistance may offer an efficacious avenue.

Figure 2.

Combinations involving targeted metabolic reprogramming. (a) Single targeted agents are frequently directed at a specific biological feature (e.g. oncogenic signalling node) of the tumour but with so much redundancy and crosstalk across these pathways, many of which lead to the metabolic reprogramming of cells, resistance can frequently occur. (b) One dual‐targeting strategy to account for redundancy in signalling pathways and the common feature of metabolic reprogramming of the tumour is to target a source feature (i.e. signalling node) and a key metabolic reprogramming event fed by this node. (c) More specifically, patients can be typed for both classic oncogenic activators and the key metabolic features of the tumour and subsequently dosed with a highly specific first‐line regimen.

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Stirdivant, Steven, Milburn, Michael, Eckhart, Andrea, and Beebe, Kirk(Dec 2013) Understanding Tumour Metabolic Reprogramming with Metabolomics. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0025297]