350P - Antitumor activity of dual PI3K and ER blockade in ER positive breast cancer models

Date 29 September 2012
Event ESMO Congress 2012
Session Poster presentation I
Topics Basic Science
Breast Cancer, Metastatic
Presenter Jessica Tao
Authors J. Tao1, M. Scaltriti1, S. Marlow1, M. Elkabets1, N. Morse1, D. Sgroi2, J. Baselga1
  • 1Cancer Center, Massachusetts General Hospital, 02129 - Charlestown/US
  • 2Molecular Pathology Unit, Massachusetts General Hospital, 02129 - Charlestown/US

Abstract

Background

Activation of the phosphoinositide 3-kinase (PI3K) pathway, either by receptor tyrosine kinase overexpression or PI3K/Akt/mTOR axis dysregulation, has been implicated in endocrine therapy resistance, prompting combination of PI3K inhibitors and antiestrogen therapy in the clinical setting such as in the recent BOLERO-2 study. We hypothesize that dissecting the molecular crosstalk between the PI3K and estrogen receptor (ER) pathways will help define the subset of patients most responsive to combined PI3K/antiestrogen therapy.

Methods

ER+ cell lines MCF7, MCF7-long term estrogen deprived (LTED), MCF7-fulvestrant resistant clones Fslx64 and Fslx70, T47D, ZR75-1, CAMA1, MDA361, KPL-1, BT474, EFM19, HCC1428, UACC812, were treated with the ER degrader, fulvestrant, and the p110α-specific PI3K inhibitor BYL719 in vitro. Cell viability was measured by CellTiter-Glo and Crystal Violet. MCF7 and ER+ patient-derived xenografts were treated with fulvestrant, BYL719 or the combination in vivo. Protein expression was measured by Western blot and immunohistochemistry.

Results

Fulvestrant or BYL719 treatment resulted in variable inhibition of cell viability in all ER+ cell lines. Combination treatment was significantly superior to monotherapy in MCF7, MCF7-LTED, MCF7-Fslx64 and MCF7-Fslx70. While MCF7 clones Fslx64 and Fslx70 were resistant to >1 µM of fulvestrant, they were exquisitely sensitive to BYL719. Moreover, PI3K inhibition led to ER upregulation in ER+ cell lines, including those most sensitive to combination treatment. Total ER levels also increased in MCF7 xenografts treated with therapeutic doses of BYL719.

Conclusions

Combined treatment with BYL719 and fulvestrant in vitro was superior to single-agent treatment in 4 of 13 ER+ cell lines. Importantly, dual PI3K/ER blockade was effective in cells resistant to ER deprivation and/or degradation. Induced ER levels following PI3K suppression may represent a feedback mechanism by which ER+ cells escape PI3K inhibition. We are currently studying whether this phenomenon predicts sensitivity to dual PI3K/ER blockade in ER+ breast cancer models.

Disclosure

J. Baselga: J. Baselga is a consultant/advisory board member for Aragon, AstraZeneca, Sanofi, Bayer, Onyx, Chugai, Constellation, Exelixis, Intellikine, Merck, Novartis, and Roche Genentech.

All other authors have declared no conflicts of interest.