Autophagy-targeted intervention synergized with pegaspargase: an innovative therapeutic paradigm for pancreatic cancer

Pegaspargase is a pegylated asparaginase formulation used in hematological malignancies. However, its application in solid tumors is greatly limited due to inherent drug resistance nature of solid tumors. Poor prognosis and lack of effective treatment options for pancreatic cancer urgently necessitate the exploration of novel therapeutic approaches. In the present study, we analyzed pegaspargase's cytotoxicity on pancreatic cancer cells (SU.86.86 and BxPC-3) in vitro. Then we evaluated the level of autophagy and related pathway proteins during treatment. Finally, we aimed to evaluate the effect of autophagy modulator on pegaspargase efficacy both in vitro and in vivo. The results revealed that pegaspargase (4 IU/mL) decreased the viability of SU.86.86 and BxPC-3 cells and induced apoptosis rates of 28.7% and 16.9%, respectively. Pegaspargase activated autophagy and downregulated Akt/mTOR path-way. Furthermore, autophagy inhibitors increased the cytotoxicity of pegaspargase (4 IU/mL) on SU.86.86 and BxPC-3 cell lines and induced apoptosis rates of 39.9% and 21.9%, respectively. In vivo evaluation confirmed that autophagy inhibition enhanced the antitumor efficacy of pegaspargase. In conclusion, our research demonstrated that combining pegaspargase with autophagy inhibition is a promising approach in pancreatic cancer clinical treatment.