Targeting PI3K/Akt/mTOR signaling in cancer is an attractive therapeutic option, and particular the block of Akt can inhibit tumor growth. Ipatasertib (GDC-0068) is a potent inhibitor of all three Akt isoforms in in vitro and in vivo human tumormodels with activated Akt signaling, exhibiting a specific activity on mutant Akt1. Two ongoing trials are evaluating the efficacy of ipatasertib in combination with paclitaxel in neoadjuvant (NCT02301988) or in first line (NCT02162719) therapy in triple negative breast cancer patients. We investigated the role of ipatasertib in combination with anti-microtubule agents vinorelbine, taxanes, and eribulin in breast cancer cell lines.
The efficacy of combined treatment of Ipatasertib (GDC-0068) plus vinorelbine/taxanes/eribulin was evaluated in in vitro models of all breast cancer subtypes (HR and HER2 +/-, Akt wild-type/mutant). We assayed cell proliferation by using MTT (3,(4,5-dimethylthiazol-2)2,5 difeniltetrazolium bromide) and apoptosis by flow-cytometry analysis. The effect on the activation status of proteins downstream of Akt (phospho-S6, S6, phosphor-4EBP1, 4EBP1) and on other intracellular pathways (phospho-MAPK, MAPK, phosphor-MEK, MEK, cleaved PARP, caspase 3, Bcl-2) was analyzed by Western Blot analysis.
A significant synergism of ipatasertib and chemotherapy in terms of anti-proliferative and pro-apoptotic effect was registered, irrespective of HR expression, HER2, and PI3KCA mutational status. These effects were accompanied by inhibition of Akt and MAPK pathways and activation of pro-apoptotic proteins, such as cleaved PARP and caspase 3.
Targeting downstream signaling by blocking Akt with ipatasertib could represent a new strategy to enhance chemotherapy effects in breast cancer models.
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Second University of Naples
All authors have declared no conflicts of interest.