Shim and colleagues from Johns Hopkins School of Medicine in Baltimore, the National Cancer Institute in Bethesda, and Emory University School of Medicine in Atlanta have recently shown that the HIV protease inhibitor nelfinavir (Viracept) is a selective inhibitor of HER2-positive breast cancer cells.
After nelfinavir was identified as a selective inhibitor of HER2-positive cells in pharmacologic profiling of seven genotypically distinct breast cancer cell lines from a screen of the Johns Hopkins Drug Library, a genome-wide screen of a haploinsufficiency yeast mutant collection was performed to identify the molecular targets of nelfinavir. It was found that nelfinavir inhibited heat shock protein (HSP)90 function in breast cancer cells through a novel mechanism.
Evaluation of the antitumor activity of nelfinavir in xenografts in athymic nude mouse models of breast cancer showed significant inhibitory effects: The mean tumor volume index of HCC1954 cells on day 29 was 14.42 for vehicle and 5.16 for nelfinavir (P < .001), and the mean tumor volume index of BT474 cells on day 26 was 2.21 vs 0.90 (P < .001). In addition, nelfinavir inhibited the growth of trastuzumab (Herceptin)- and/or lapatinib (Tykerb)-resistant HER2-positive breast cancer cells in vitro at clinically achievable concentrations.
As concluded by the investigators, “Nelfinavir was found to be a new class of HSP90 inhibitor and can be brought to HER2-breast cancer treatment trials with the same dosage regimen as that used among HIV patients.” ■
Shim JS, et al: J Natl Cancer Inst 104:1576-1590, 2012.