Aggravation of Er Stress By Combination of Proteasome Inhibitors and Hiv Protease Inhibitors Results in Preferencial Killing of Triple-Negative Breast Cancer Cells in Vitro

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.