The efficacy of single node inhibitors is limited by several factors which promote persistent or reactivated PI3K/AKT/mTOR signalling, including (i) pathway reactivation by feedback activation or bypass signalling, (ii) the presence of co-occurring pathway mutations beyond the targeted node [4], and (iii) systemic perturbations in glucose homeostasis that lead to hyperinsulinemia and pathway reactivation (summarised in Supplementary Fig. S1a). Here, PIK3CG is linked to hyperinsulinism.