In vitro proteotoxic synergism of nelfinavir and carfilzomib in solid cancer cell lines

Automatisch geschlossen · 2013 bis 2014

Monozentrisch am KSSG
Automatisch geschlossen
Fördermittel KSSG
Schlagwörter (Tags)
ER-stress; proteasome inhibition; HIV protease inhibitors; solid carcinomas
Weitere Informationen
In 2013, several experiments with breast cancer cell lines were successfully performed by Dr. J. Gibbons-Marsico under the guidance of Dr. M. Kraus of the Laboratory for Experimental Oncology. We used the triple-negative breast cancer cell line MDA-MB-468 and the HER2-positive, ER-negative breast cancer cell line BT-474. In the MDA-MB-468 cell line, substantial synergistic cell killing was found in conventional MTS assays with the combination of carfilzomib and both nelfinavir as well as the alternative HIV-protease inhibitor lopinavir (combination index <<1.0). This has been confirmed in corresponding Western Blot assays (work ongoing). Similarly, substantial cell killing has been observed in the HER2-positive breast cancer cell line BT-474.

HER2-positive breast cancer accounts for approximately 25-30% of all breast cancer cases, and carries a bad prognosis compared to HER2-negative breast cancer. Despite recent advances with the development of HER2-targeted treatments, mainly trastuzumab and lapatinib, there is universal development of drug resistance in patients with advanced HER2-positive breast cancer, and a high unmet medical need to develop new innovate drugs for these patients. Nelfinavir has been shown to have anticancer properties by inducing cellular endoplasmatic reticulum (ER) stress, and this effect can be potentiated by the combined administration of the proteasome inhibitor bortezomib. Carfilzomib is the first irreversible and highly potent proteasome inhibitor, that has recently been approved for refractory multiple myeloma by the FDA. Based on previous preclinical work in HER2-positive breast cancer, the combination of nelfinavir and carfilzomib is suggested to have substantial cytotoxic activity in HER2-positive breast cancer cells, primarily by inducing ER-stress and by the inhibition of AKT-signaling and heat-shock proteins. Accordingly, this study assesses the potential synergism of nelfinavir and carfilzomib in HER2-positive breast cancer cells, as this has not been explored so far. If successful, a phase 1 study will be planned in patients with advanced breast cancer to assess the clinical activity of this drug combination.