HIV agent offers HER2-positive breast cancer hope

Oct 15 2012

By Lynda Williams, Senior medwireNews Reporter

A drug used to treat HIV infection may be a new treatment line for patients with an aggressive type of breast cancer, US researchers believe.

In vitro findings show that the aspartyl protease inhibitor, nelfinavir, selectively inhibits growth of HER2-positive breast cancer cells in vitro and in vivo, including cell lines with proven resistance to the current HER2-positive agents trastuzumab and/or lapatinib.

"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 HER2 breast cancer patients," say Jun Liu and co-workers from Johns Hopkins School of Medicine in Baltimore, Maryland.

As reported in the Journal of the National Cancer Institute, nelfinavir was shown to selectively inhibit HER2-positive breast cancer cell lines via phosphorylation of the proteins AKT, ERK1, ERK2, and HER2. The researchers also demonstrate that nelfinavir binds HSP90 at the C-terminal and induces conformational changes in the protein; this is a different mechanism from other HSP90 inhibitors.

When nelfinavir was given to nude mice carrying xenograft HER2-positive tumors at an intraperitoneal dose of 25 mg/kg, or an oral dose of 40 mg/kg, there was a significant decrease in tumor growth compared with animals given a control treatment. No such effect was noted for mice carrying HER2-negative xenograft tumors.

Finally, the researchers demonstrated that nelfinavir was able to inhibit in vitro proliferation of two breast cancer cell lines with intrinsic and acquired resistance to trastuzumab, and a third cell line with intrinsic resistance to both trastuzumb and lapatinib, with half maximal inhibitor concentrations (IC50s) of 4.74-6.44 µM.

Current nelfinavir regimens achieve a peak plasma dose of 8-10 µM, explains the team, "suggesting that it may be effective in breast cancer patients with the current dosage regimen."

Liu et al therefore conclude: "The discovery of HER2 selective inhibition of breast cancer cells by nelfinavir and the elucidation of its unique mode of action through binding to a new site on HSP90 have important implications in the development of nelfinavir and its analogs as new anticancer agents."

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