Overcoming Erlotinib Resistance In EGFR Mutationpositive Lung Adenocarcinomas By Targeting Phosphoglycerate Dehydrogenase(PHGDH)

Although the epidermal growth factor receptor tyrosine kinase inhibitors（EGFR-TKIs）,such as erlotinib,have shown dramatic effects in EGFR mutation lung adenocarcinomas（LADC）,patients become resistant by various mechanisms,including EGFR second mutation and bypass signaling reactive etc,thereafter relapsing,which is the biggest hurdles to the clinical use of TKIs drugs.Accumulating evidence has revealed that metabolic reprogramming played role in drug resestance.Phosphoglycerate dehydrogenase（PHGDH）,associated with tumorigenesis and tumor progression,plays a critical role in redirecting the glycolytic intermediate,3-phosphoglycerate（3-PG）,to the serine synthesis pathway（SSP）.High expression of PHGDH predicts poor prognosis in LADC.Nevertheless,the relationship between PHGDH and erlotinib resistance in LADC remains largely unclear.The results in vivo and vitro showed that:compared to the parental cells,1.Erlotinib resistant（ER）cells remain high uptake of exogenous serine for cellular proliferation.2.The level of PHGDH increased significantly in the PC9ER cells.3.Blocking PHGDH by si PHGDHs transfection or inhibitors inhibited cells growth and restored sensitivity to erlotinib in the PC9ER4 cells in the complete medium.Perturbation PHGDH by sh PHGDH suppressed xenograft tumor growth combination with erlotinib in significant augmentation of inhibition effect.4.PHGDH inhibition reduced mitochondrial and cytoplasmic pathways,decreased GSH levels,showed higher induction of reactive oxygen species（ROS）,elevated phosphorylatedand H2AX on Ser¹³⁹,and induced apoptosis.5.The ROS scavengers,N-acetyl-cysteine（NAC）could reverse complex ROS andγH2AX.The results demonstrated that suppression of PHGDH induce ROS overproduction,elevatedγH2AX,leading cell apoptosis.Collectively,our study indicated that PHGDH play important role in erlotinib adaptive resistance cells.A combination of erlotinib and PHGDH inhibitions has potential therapeutic value in LADC.