72P - Targeting ER stress by the combination of proteasome inhibitors and HIV protease inhibitors in preclinical models of triple-negative breast cancer

Date 08 May 2014
Event IMPAKT 2014
Session Welcome reception and Poster Walk
Topics Drug Development
Breast Cancer
Presenter Jennifer Gibbons Marsico
Citation Annals of Oncology (2014) 25 (suppl_1): i25-i27. 10.1093/annonc/mdu071
Authors J. Gibbons Marsico1, T. Heger2, M. Kraus2, C. Driessen1, M. Jörger1
  • 1Oncology & Haematology, Cantonal Hospital St. Gallen, 9007 - St. Gallen/CH
  • 2Clinical Trials Unit, Cantonal Hospital St. Gallen, 9007 - St. Gallen/CH

Abstract

Background:

Recurrent triple-negative breast cancer (TNBC) is a condition of high unmet medical need, due to its aggressive biology, fast development of drug resistance, and lack of molecular targets. Until now, chemotherapy remains the standard of care for advanced TNBC, with a poor median overall survival. Recently, pharmacological aggravation of endoplasmic reticulum stress (ERS) has become an attractive strategy not only for multiple myeloma, but also for solid malignancies.

Methods:

We determined the cytotoxic activity of proteasome inhibitors (bortezomib, bzb; carfilzomib, cfz) alone and in combination with the two HIV protease inhibitors nelfinavir (nel) and lopinavir (lop) in three different TNBC cell lines (BT 549, MDA-MB 231, MDA-MB 468). To assess cytotoxicity, the 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTS) assay was applied.

Results:

Both proteasome inhibitors moderately reduced cell survival in all TNBC cell lines at clinically relevant concentrations (125 nM) when applied alone (21%–44%). At increased concentrations (1 uM), the irreversible proteasome inhibitor cfz exhibited even higher cytotoxicity (>80%) than bzb (>60%) in all tested cell lines. Importantly, combinations with HIV protease inhibitors yielded significantly enhanced cytotoxicity and mostly synergistic responses in all cell lines compared with either proteasome (table: cytotoxic effects of mono and combination experiments) or HIV protease inhibitors alone. Moreover, preliminary data using combinations with other HIV protease inhibitors showed similar cytotoxic effects.

Conclusions:

Drug combinations of the irreversible proteasome inhibitor carfilzomib and HIV protease inhibitors such as lopinavir or nelfinavir 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 phase1B-2 clinical study is in early planning.

Bzb/- Bzb/Nel Bzb/Lop Cfz/- Cfz/Nel Cfz/Lop
MDA-MB 468 27 +/− 8 90 +/− 2 84 +/− 1 21 +/− 7 88 +/− 2 84 +/− 4
MDA-MB 231 36 +/− 8 87 +/− 5 85 +/− 0.2 41 +/− 2 87 +/− 4 85 +/− 4
BT549 23 +/− 3 92 +/− 1 80 +/− 0.2 44 +/− 3 92 +/− 1 85 +/− 4

(% cell death +/− SD)

Disclosure:

All authors have declared no conflicts of interest.