Mechanisms And Applications Of Synergistic Anti-tumor Therapy With Fasting And PARP Inhibitors

Objective: With the development of precision medicine,small-molecule targeted therapy has become a pillar of cancer treatment.Being characterized by high genomic instability,tumors such as ovarian cancer and breast cancer usually harbor mutations responsible for homologous recombination repair deficiency(HRD),which provides a new opportunity for targeting the synthesis of poly(ADP-ribose)polymerase(PARP)to induce tumor cell death.Therefore,several PARP inhibitors have been approved for the clinical treatment of HRD tumors.However,long-term treatment with PARP inhibitors leads to drug resistance,limiting the benefits for patients.Previous studies have shown that starvation therapy,such as the low-glucose diet,can significantly reverse chemotherapy resistance in cancers.However,little is known about whether PARP inhibitors can reprogram the metabolism of tumor cells and whether starvation therapy can sensitize PARP inhibitors to tumors.Therefore,this study aims to explore the mechanism underlying the reprogramming of tumor metabolism by PARP inhibitors,identify metabolic targets that sensitize PARP inhibitors and recommend feasible dietary strategies to guide the clinical management of patients receiving PARP inhibitor treatment.Methods: This study relied on a multicenter,single-arm,prospective,Phase II clinical trial of neoadjuvant niraparib for advanced ovarian cancer(NANT: NCT04507841),collecting paired patient tissue samples before and after treatment with niraparib,collecting postoperative triple negative breast cancer(TNBC)tissues,and including cell lines with different BRCA gene mutation backgrounds.The study also constructed primary tumor cell culture models,patient-derived xenografts(PDX)models,cell-derived xenografts(CDX)models,and the biobank.Animal Positron Emission Computed Tomography(PET-CT)imaging technology was used to evaluate changes in tumor tissue metabolism caused by PARP inhibitors;flow cytometry was used to detect tumor cell metabolic changes induced by PARP inhibitors;the Seahorse XF analysis system was used to detect tumor cell energy metabolism modes;metabolic-related tests were conducted using the metabolic product and enzyme test kits;real-time quantitative polymerase chain reaction,flow cytometry,Western blot,immunohistochemistry,and immunofluorescence were used to detect gene and protein expression levels in cells and tissues.Drug sensitivity analysis was performed by detecting cell proliferation and apoptosis.Small molecule inhibitors were used to explore changes in relevant molecular pathways.Based on the molecular mechanisms explored in vitro,a glucose starvation diet plan was constructed,and its efficacy and safety in combination with PARP inhibitors were further evaluated in animal experiments.Results: Mechanistically,PARP inhibitors can activate the p-AMPK-TXNIP-GLUT1 pathway to significantly increase glucose uptake in tumor cells,and then activate mitochondrial metabolism to produce α-Ketoglutarate(α-KG)through the NAD+-SIRT1-PGC1α signaling axis,thereby reversing the HRD state and mediating PARP inhibitor resistance.Glucose deprivation in vitro can restore the sensitivity of tumor cells to PARP inhibitors.In terms of application,a low-glucose diet and intermittent fasting glucose starvation diet plan were constructed,and PARP inhibitors were combined with treatment in HRD-positive mouse CDX and PDX tumor models,reducing blood glucose to promote PARP inhibitor-mediated tumor cell killing,reversing acquired resistance,and alleviating PARP inhibitor-induced hypertension without exacerbating other drug toxicities.Conclusions: 1.PARP inhibitor-induced elevation of glucose uptake and reprogramming of metabolism in tumors result in the impairment of its therapeutic efficacy,thus innovatively revealing the metabolic regulation mechanism of PARP inhibitor resistance.2.Low glucose and intermittent fasting can enhance the therapeutic efficacy of PARP inhibitors and reduce side effects,providing a new feasible combination of sensitization and diet management for the long-term maintenance treatment of PARP inhibitors.