Drug combinations and methods for inhibiting insulin receptor substrate and PI3K/AKT/mTOR signaling pathways are provided. The present invention relates to inhibition of a PI3K (phosphatidylinositol kinase (Phosphoinositide 3-kinase)/AKT (protein kinase B)/mTOR (mammalian target of rapamycin) signaling pathway for treating or preventing a disease. More particularly, the invention relates PRCP (prolylcarboxypeptidase) antagonist (i.e. anti-PRCP agent), or PREP (prolyl endopeptidase) antagonist (i.e., anti-PREP agent), or a pharmaceutical composition of PREP/PRCP dual antagonist, a pharmaceutical composition comprising PREP antagonist or PRCP antagonist drugs and mTOR antagonists, or a pharmaceutical composition comprising PRCP and PREP dual antagonists and mTOR antagonist. The present invention also relates to the aforementioned pharmaceutical composition for treating or preventing diseases associated with activated PI3K/AKT/mTOR signaling pathway. Furthermore, the present invention also relates to the molecular mechanisms of stability and degradation of the insulin receptor substrate proteins and the use of PRCP antagonists, PREP antagonists, dual antagonists of PREP and PRCP for degradation of insulin receptor substrate proteins for treatment.