Combinational Therapy For The Treatment Of Triple-Negative Breast Cancer

Combination therapy from the perspective of metabolism is a promising option for treating TNBC.Ferroptosis is a novel iron-dependent regulated cell death pathway and is closely with tumour inhibition.The aim of this thesis was to investigate into the feasibility of five types of ferroptosis-based combination therapy for TNBC treatment.First,we presume that mitochondrial metabolism can be exploited by targeting BTB and CNC homology1(BACH1)to sensitize TNBC to ferroptosis therapy.Hemin and RSL3 was as the BACH1 inhibitor and ferroptosis inducer,respectively.The cell viability study demonstrated no synergism existed between RSL3 and hemin in MDAMB-231 cells.Second,BACH1 inhibition can increase the production of guanosine-5’-triphosphate(GTP)whose hydrolysis is key to control the dynamic instability of microtubules.Then we found that the model microtubule inhibitor,paclitaxel can synergize with hemin to enhance the cytotoxicity.However,the actual mechanisms still need further investigation.Third,ferroptosis is associated with the accumulation of tailored lipid peroxides,resulting in the phosphorylation of plateletderived growth factor β-receptor(PDGFR-β)that is a subclass of receptor tyrosine kinases(RTK).It was revealed that RTK inhibitor(Crizotinib)showed antagonism with RLS3.The interaction between PDGFR-β inhibitor(Sunitinib)show synergisms only under certain ratios.Last,AMPK signalling can reduce the synthesis of polyunsaturated fatty acids(PUFA).PUFA is the key building block of tailored lipids to further induce ferroptosis.Therefore,AMPK activation induces ferroptosis resistance.To address this,it was presumed that the combination of GPX4 inhibitor and a typical PUFA(e.g.arachidonic acid(AA))can reverse the resistance.The data showed that AA indeed sensitized the action of Fin56,a model GPX4 inhibitor.To sum up,the TNBC shows unique tumour microenvironment with limited treatment option.five types of metabolism-based combination therapies were assessed at the cellular level.The current work may open new avenues of novel TNBC therapies.