The systemic toxicities of oral PI3K/Akt inhibitors, including gastrointestinal effects, hyperglycemia, and skin rashes, have driven next-generation approaches against the PI3K/Akt pathway such as Akt degraders, inhalation-based drug delivery, prodrugs, and fibroblast-specific conjugates to enhance target selectivity and reduce adverse effects. This evidence concerns the gene AKT1 and Skin rash.