Metabolic Fingerprinting Links Oncogenic PIK3CA with Enhanced Arachidonic Acid-Derived Eicosanoids

Oncogenic transformation is associated with profound changes in cellular metabolism, but whether tracking these can improve disease stratification or influence therapy decision-making is largely unknown. Using the iKnife to sample the aerosol of cauterized specimens, we demonstrate a new mode of real-time diagnosis, coupling metabolic phenotype to mutant PIK3CA genotype. Oncogenic PIK3CA results in an increase in arachidonic acid and a concomitant overproduction of eicosanoids, acting to promote cell proliferation beyond a cell-autonomous manner. Mechanistically, mutant PIK3CA drives a multimodal signaling network involving mTORC2-PKCζ-mediated activation of the calcium-dependent phospholipase A2 (cPLA2). Notably, inhibiting cPLA2 synergizes with fatty acid-free diet to restore immunogenicity and selectively reduce mutant PIK3CA-induced tumorigenicity. Besides highlighting the potential for metabolic phenotyping in stratified medicine, this study reveals an important role for activated PI3K signaling in regulating arachidonic acid metabolism, uncovering a targetable metabolic vulnerability that largely depends on dietary fat restriction. [Display omitted] [Display omitted] •The iKnife offers near real-time diagnosis of PIK3CA mutant breast cancers•Oncogenic PIK3CA promotes enhanced arachidonic acid via mTORC2-PKCζ-cPLA2 signaling•Mutant PIK3CA regulates proliferation beyond a cell autonomous manner•cPLA2 inhibition and dietary fat restriction suppress PIK3CA-induced tumorigenicity Metabolic fingerprinting using the iKnife offers near real-time diagnosis of PIK3CA mutant breast cancers and connects oncogenic PIK3CA with enhanced arachidonic acid metabolism. cPLA2 inhibition shows remarkable synergy with dietary fat restriction to restore tumoral immune cell infiltration and inhibit growth of mutant PIK3CA-bearing breast tumors.