Predicting The Sensitivity Of Ovarian Cancer To Paclitaxel And S63845 Based On Intracellular BAK-MCL1 Complex

Ovarian cancer has the highest mortality rate among various types of gynecological tumors.Many ovarian cancer patients are treated with treatments including paclitaxel or platinum,however,the response rate is not high.The prediction of drug sensitivity could effectively improve the quality of life or lifespan.The methods for predicting tumor drug sensitivity include gene sequencing,drug screening in vitro,PDX models,and so on.BCL2 family proteins control the mitochondrial apoptotic pathway,and are involved in many cancer treatments induced apoptosis.Several methods have used BCL2 family proteins for anti-cancer drug sensitivity predictions,such as predictions based on BCL2 family protein expression levels,and Dynamic BH3 profiling.Previous studies in our group have demonstrated BAK constitutively activated status(BAK status)predicts sensitivities of BH3 mimetics in lymphohematopoietic cells.However,it is not clear whether BAK status could predict cancer cell sensitivity to other chemotherapy drugs or in other cancer types.In this study,BAK status was explored to predict sensitivities to other chemotherapy drugs in ovarian cancer.We found that BAK has four states(BAK/BCLXL,BAK/MCL1,BAK/BCLXL+BAK/MCL1,and not constitutively activated)in ovarian cancer cell lines,which were detected by immunoprecipitation.Among the different status,cells with BAK/MCL1 complexes were more sensitive to paclitaxel,S63845,and carboplatin,while cells with BAK/BCLXL complexes were more resistant to 5-FU.The correlation of BAK/MCL1 cells with sensitivity to paclitaxel was the most significant among all the drugs.Moreover,BAK status is better than single BCL2 family protein expressions in the prediction of paclitaxel sensitivity in ovarian cancer cells.Further studies demonstrated that BIM induced by low concentration of paclitaxel preferentially binds to MCL1 over BCLXL,providing a possible mechanism for that cells bearing BAK/MCL1 are more sensitive to paclitaxel.Furthermore,S63845 could enhance the efficacy of paclitaxel in BAK/MCL1 cells rather than cells that do not have BAK/MCL1 cells in vitro.The in vivo experiments also suggest S63845 enhance paclitaxel efficacy in tumors bearing BAK/MCL1 complexes.In summary,the existence of BAK/MCL1 complexes could be a predictive marker for paclitaxel,S63845,or its combination in ovarian cancer.