387P - Aggravation of ER stress by combination of proteasome inhibitors and HIV protease inhibitors results in preferencial killing of triple-negative bre...

Date 27 September 2014
Event ESMO 2014
Session Poster Display session
Topics Drug Development
Basic Science
Breast Cancer, Metastatic
Presenter Jennifer Gibbons Marsico
Citation Annals of Oncology (2014) 25 (suppl_4): iv116-iv136. 10.1093/annonc/mdu329
Authors J. Gibbons Marsico1, T. Heger2, M. Kraus3, M. Joerger1, C. Driessen1, T.T. Cerny1
  • 1Oncology And Haematology, Hospital Cantonal St Gallen, 9007 - St. Gallen/CH
  • 2Research, EMPA Swiss Federal Laboratories for Materials Science and Technology, 9014 - St. Gallen/CH
  • 3Laboratory Of Experimental Oncology, Hospital Cantonal St Gallen, 9007 - St. Gallen/CH

Abstract

Aim

Breast cancer (BC) is the most frequent cancer and the principal cause of cancer death for females worldwide. Triple-negative breast cancer (TNBC), carries extraordinarily poor prognosis due to its aggressive biology, fast development of drug resistance, and lack of molecular targets such as hormone receptors and HER2/Neu. Until now, chemotherapy remains the standard care for advanced TNBC, with a poor median overall survival. Recently, pharmacological aggravation of endoplasmic reticulum stress (ERS) has become an attractive strategy for cancer therapy. In our work we present evidence that pharmacological aggravation of ERS may lead to efficient killing of breast cancer preclinical models in vitro.

Methods

We determined the cytotoxic activity of proteasome inhibitors (bortezomib, bzb; carfilzomib, cfz) alone and in combination with the two HIV protease inhibitors nelfinavir (nfv) and lopinavir (lpv) in five different breast cancer cell lines. To assess cytotoxicity of each drug and their combinations, the MTS assay was applied.

Results

Both proteasome inhibitors moderately reduced cell survival in all BC cell lines at clinically relevant concentrations (125 nM) when applied alone (8% - 36%). Importantly, combinations with HIV protease inhibitors yielded significantly enhanced cytotoxicity in all cell lines compared with either proteasome (see table) or HIV protease inhibitors alone. Moreover, preliminary data shows that these combinations cause strong cytotoxic effects in TNBC cell lines.

Conclusions

Drug combinations of the irreversible proteasome inhibitors and an HIV protease inhibitor resulted in substantial cytotoxicity in preclinical models of TNBC. The concept of pharmacological aggravation of ERS is promising in patients with TNBC, and a respective phase IB-II clinical study is in early planning.

Cell Lines Bzb (125 nM) Cfz (125 nM)
- Nfv Lpv - Nfv Lpv
MDA-MB 468 27 ± 8 57 ± 0.1 80 ± 1 21 ± 7 65 ± 2 79 ± 4
MDA-MB 231 36 ± 8 56 ± 0.1 57 ± 2 41 ± 2 74 ± 4 78 ± 8
BT 549 23 ± 3 90 ± 1 56 ± 0.2 44 ± 3 91 ± 1 69 ± 4
BT 474 8 ± 6 28 ± 6 32 ± 3 33 ± 6 82 ± 6 61 ± 1
SK-BR-3 - - - 30 ± 2 68 ± 3 21 ± 4

Cytotoxic effects of mono and combination experiments in BC cell lines (% cell death +/- SD)

Disclosure

All authors have declared no conflicts of interest.