Abstract
PurposeThe Phosphatidylinositol 3-kinase (PI3Ks) pathway is commonly altereted in breast cancer patients, but its role is still unclear. Taselisib, a mutant PI3Kα selective inhibitor, and ipatasertib, an AKT inhibitor, are currently under investigation in clinical trials in combination with paclitaxel or hormonal therapies in breast cancer. The aim of this study was to evaluate if PI3K or AKT inhibition can prevent resistance to chemotherapy and potentiate its efficacy.Experimental designThe efficacy of combined treatment of ipatasertib and taselisib plus vinorelbine or paclitaxel or eribulin was evaluated in vitro on human breast cancer cells (with different expression profile of hormonal receptors, HER2, and of PI3Ka mutation) on cell survival by using MTT (3,(4,5-dimethylthiazol-2)2,5 difeniltetrazolium bromide) and colony forming assays on cell apoptosis by flow-cytometry analysis. We also investigated the effect of combined treatment on downstream intracellular signaling, by western blot analysis, and on metastatic properties, by migration assays. Finally, we analyzed changes in cell cytoskeleton by immunofluorescence.ResultsA significant synergism of ipatasertib or taselisib plus anti-microtubule chemotherapy in terms of anti-proliferative, pro-apoptotic and anti-metastatic effect was observed. The combined treatment completely inhibited the activation of proteins downstream of PI3K and MAPK pathways and affected the expression of survivin. Combined treatments completely disorganized the cytoskeleton in human breast cancer cells, with contemporary delocalization of survivin from cytoplasm to nucleus, thus suggesting a potential mechanism for this combination.ConclusionsTargeting PI3K may enhance the efficacy of anti-microtubule drugs in human breast cancer cells.
Highlights
Breast cancer (BC) is the most frequent cancer among women with an estimated 1.6 million new cancer cases diagnosed in 2012 [1]
Targeting Phosphatidylinositol 3-kinase (PI3Ks) may enhance the efficacy of anti-microtubule drugs in human breast cancer cells
MDA-MB231 and MDA-MB468 cells were selected as control, since they are human breast adenocarcinomaderived cell lines harbouring PI3K wild-type gene
Summary
Breast cancer (BC) is the most frequent cancer among women with an estimated 1.6 million new cancer cases diagnosed in 2012 [1]. Despite the recently observed reduction in mortality due to early diagnosis and improvement of treatment strategies, BC continues to be the leading cause of neoplastic death in women, regardless of age, and long-term survival of metastatic breast cancer (MBC) patients remains 43–50 months for HER2 positive disease and 30–45 months for HER2 negative and HR positive subtypes [4, 5]. Modern cancer therapies for breast cancer include chemoterapeutic, anti-hormonal and molecular agents [6,7,8,9]. Research has been focused on mechanisms of resistance to conventional therapies in terms of intrinsic or acquired molecular defects involving intracellular signal transduction pathways in order to detect new targetable oncogenetic proteins [10] Different classes of chemoterapic agents are currently approved for treatment of metastatic BC: antracylines, anti-mitotic agents (including taxanes, vinorelbine, eribulin), alkylating agents (such as cisplatin and carboplatin) and anti-metabolites (5-fluorouracile, capecitabine, and gemcitabine) [7,8,9].
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