Oncotarget

Research Papers:

Phosphatidylinositol 3-kinase (PI3Kα)/AKT axis blockade with taselisib or ipatasertib enhances the efficacy of anti-microtubule drugs in human breast cancer cells

Floriana Morgillo _, Carminia Maria Della Corte, Anna Diana, Concetta di Mauro, Vincenza Ciaramella, Giusi Barra, Valentina Belli, Elisena Franzese, Roberto Bianco, Evaristo Maiello, Ferdinando De Vita, Fortunato Ciardiello and Michele Orditura

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Oncotarget. 2017; 8:76479-76491. https://doi.org/10.18632/oncotarget.20385

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Abstract

Floriana Morgillo1, Carminia Maria Della Corte1, Anna Diana1, Concetta di Mauro2, Vincenza Ciaramella1, Giusi Barra3, Valentina Belli1, Elisena Franzese1, Roberto Bianco2, Evaristo Maiello4, Ferdinando De Vita1, Fortunato Ciardiello1 and Michele Orditura1

1Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale “F. Magrassi”, Università degli Studi della Campania “Luigi Vanvitelli”, Napoli, Italy

2Oncologia Medica, Dipartimento di Medicina Clinica e Chirurgia, Università degli Studi di Napoli “Federico II”, Napoli, Italy

3Immunologia Clinica, Dipartimento di Internistica Clinica e Sperimentale “F. Magrassi”, Università degli Studi della Campania “Luigi Vanvitelli”, Napoli, Italy

4IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy

Correspondence to:

Floriana Morgillo, email: [email protected], [email protected]

Keywords: AKT, breast cancer, taselisib, ipatasertib, novel drugs

Received: March 22, 2017     Accepted: July 26, 2017     Published: August 22, 2017

ABSTRACT

Purpose: The 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 design: The 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.

Results: A 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.

Conclusions: Targeting PI3K may enhance the efficacy of anti-microtubule drugs in human breast cancer cells.


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PII: 20385