PIK3CD and neoplasm: In addition, there are other factors leading to resistance mechanisms such as a high level of purine-related metabolites, elevated glycolysis with dysregulated mitochondrial signaling leading to loss of PTEN and PPP2R2B expression in response to dual PI3K/mTOR inhibitors [121,122,123], macrophages in the tumor microenvironment contributing to PI3K inhibitor resistance via the NFĸB pathway [124], and lack of PI3K mutant-specific inhibitors currently available [45].