16P - Phosphatidylinositol 3-kinase (PI3Kα)/AKT axis blockade with taselisib or ipatasertib enhances the efficacy of anti-microtubule drugs in human brea...

Date 11 September 2017
Event ESMO 2017 Congress
Session Poster display session
Topics Basic Science
Breast Cancer
Presenter Anna Diana
Citation Annals of Oncology (2017) 28 (suppl_5): v1-v21. 10.1093/annonc/mdx361
Authors A. Diana1, F. Morgillo1, C.M. Della Corte1, C. Di Mauro2, V. Ciaramella1, G. Barra3, V. Belli1, E. Franzese1, R. Bianco2, E. Maiello4, F. De Vita1, F. Ciardiello1, M. Orditura1
  • 1Dipartimento Medico-chirurgico Di Internistica Clinica E Sperimentale "f. Magrassi E A. Lanzara", Università degli Studi della Campania "Luigi Vanvitelli", 80131 - naples/IT
  • 2Dipartimento Di Medicina Clinica E Chirurgia, Università degli Studi di Napoli “Federico II”, 80131 - naples/IT
  • 3Immunologia Clinica, Università degli Studi della Campania "Luigi Vanvitelli", 80131 - naples/IT
  • 4Oncologia, IRCCS Casa Sollievo della Sofferenza, 71013 - San Giovanni Rotondo/IT

Abstract

Background

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.

Methods

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 PI3Kα mutation) on cell survival by using MTT (3,(4,5-dimethylthiazol-2)2,5 difeniltetrazolium bromide) and 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 taselib 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, thus suggesting a potential mechanism for this combination.

Conclusions

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

Clinical trial identification

Legal entity responsible for the study

Università degli Studi della Campania “Luigi Vanvitelli”, Naples, Italy.

Funding

This work has been supported by Associazione Italiana Per La Ricerca Sul Cancro (AIRC)-Project MFAG 2013-N.14392 and drugs were kindly provided by Genentech (Research proposal nr. OR-214726 for taselisib and nr. OR-214797 for ipatasertib).

Disclosure

All authors have declared no conflicts of interest.