Abstract

The PI3K /Akt pathway represents a complex signalling network that integrates numerous upstream stimuli to regulate diverse cellular processes, including cell growth, proliferation, survival, and migration. Many components of this pathway have been implicated in cancer, and several PI3K /Akt/mTOR inhibitors have been tested in clinical trials, however neither PTEN , nor PIK3CA mutation status are associated with anti-tumour response in cancer patients with advanced disease. Metabolic reprogramming is a hallmark of cancer and just as activation of the PI3K /Akt pathway leads to marked changes in cellular metabolism, recent data from our group demonstrate that dysregulated metabolism can also affect the activation of this pathway. We showed that depletion of PARK2 , a gene encoding the E3 Ligase Parkin, which has a key functional contribution in preserving mitochondrial integrity promotes the inhibition of PTEN by S-nitrosylation. Notably, this modification is important in supporting cancer cell survival and proliferation under conditions of energy deprivation.

Our efforts for tracking metabolic reprogramming in cancers with PI3K /Akt activation continue with the use of the intelligent Knife (iKnife) coupled to Rapid Evaporative Ionization Mass Spectrometry (REIMS). Gaseous ions present in the plume generated by tissue cauterization may be directly analysed, providing highly specific spectroscopic and chemometric processing that allows near-real-time characterisation of lipid metabolism. Our results demonstrate that iKnife/REIMS profiling allows a very robust metabolic classification of breast cancer into two major subtypes (lipogenic and non-lipogenic) with distinctive lipid signatures and overall lipid content. We demonstrate that the lipogenic subtype is highly enriched in PIK3CA mutations, but not loss or mutation in PTEN and depends predominantly on mTORC2 activation, opening up opportunities to investigate the mechanistic basis underlying potential metabolic vulnerabilities.