HIV drug shows activity against HER-2–positive breast cancer
The HIV drug nelfinavir inhibited HER-2–positive breast cancer cells in vitro, according to study results.
Jun O. Liu, PhD, a professor of pharmacology and molecular sciences at Johns Hopkins University School of Medicine, and colleagues highlighted a need for new therapies targeting HER-2–positive breast cancer in light of the high recurrence rates associated with that disease.
The researchers subjected seven genotypically distinct breast cancer cell lines to pharmacological profiling, then analyzed a subset of inhibitors of breast cancer cell lines from a screen of the Johns Hopkins Drug Library.
Nelfinavir (Viracept, Agouron Pharmaceuticals) was identified as a selective inhibitor of HER-2–positive cells, according to the results. The researchers used xenografts in athymic nude mouse models to assess the antitumor activity of nelfinavir.
The study drug demonstrated the ability to inhibit the growth of HER-2–positive cells in vitro.
The researchers conducted a genome-wide screen of haploinsufficiency yeast mutant collection to identify molecular targets for the drug. Results of this screening indicated that nelfinavir inhibited heat shock protein 90 function.
Nelfinavir then was characterized using proteolytic footprinting experiments. The drug demonstrated heat shock protein 90 inhibition through a novel mechanism. It selectively inhibited the growth of HER-2–positive cells (tumor volume index of HCC1954 cells on day 29, vehicle vs. nelfinavir, mean=14.42 vs. 5.16, difference of 9.25; 95% CI, 5.93-12.56; tumor volume index of BT474 cells on day 26, vehicle vs. nelfinavir, mean=2.21 vs. 0.9, difference of 1.31; 95% CI, 0.83-1.78).
Researchers also observed that nelfinavir inhibited the growth of trastuzumab- and/or lapatinib-resistant, HER-2–positive breast cancer cells in vitro at clinically achievable concentrations.
“Nelfinavir was found to be a new class of [heat shock protein 90] inhibitor,” the researchers wrote. “With a relatively low toxicity profile and much available information on its drug-drug interactions and on pharmacokinetics, Nelfinavir is ready for clinical testing in HER-2 breast cancer patients. [The findings have] important implications in the development of Nelfinavir and its analogs as new anticancer agents.”