The expression of the PAX3 and MITF genes in melanoma can cause early, nonmutational, reversible drug resistance. Melanoma tissues that express these genes can then later develop mutational, irreversible drug resistance. The HIV drug nelfinavir can prevent this targeted therapy resistance in melanoma, according to a study published in Cancer Cell.1
Nelfinivar was predicted to inhibit both PAX3 and MITF. The drug is a protease inhibitor with known antiretroviral activity.
This study examined melanoma tissue samples from 11 patients undergoing vemurafenib or dabrafenib and trametinib therapy. Samples were taken at day 0 and at days 10 to 14 of treatment. Samples were also taken at time of progression if applicable.
In patient tissue samples, cell cultures, and samples from a mouse model of melanoma, researchers revealed increased expression in PAX3 and MITF in the development of targeted therapy resistance. An immunofluorescence-based drug screen on 640 FDA-approved drugs that could inhibit PAX3 and MITF expression revealed 7 drugs that inhibit both genes. Nelfinivar had the strongest predicted effect of all 7 drugs.
In cell culture models of therapy-resistant melanoma, nelfinivar decreased PAX3 and MITF expression. It also re-sensitized the resistant cells to selumetinib treatment, a targeted therapy used to treat melanoma.
“In the first few weeks of standard treatment for skin cancer, the cancer cells become stronger and more robust against treatment,” said Claudia Wellbrock, PhD, professor of Life Sciences at The University of Manchester, Manchester, England, and lead author of the study.
“But if we can target skin cancer cells before they become fully resistant, we would have a much better chance of blocking their escape. And we think this research has brought us one step closer to making this a reality.”
These results suggested that targeting nonmutational drug resistance in melanoma could limit the development of mutational heterogeneity and resistance. Mutational resistance is irreversible, so its prevention is important.
“Thus, by targeting a cancer-type-specific master regulator that plays an important role in the initial phases of drug-induced tolerance, we identify a clinical relevant approach for melanoma therapy,” concluded the authors.
1. Smith MP, Brunton H, Rowling EJ, et al. Inhibiting drivers of non-mutational drug tolerance is a salvage strategy for targeted melanoma therapy. Cancer Cell. 2016;29(3):270-284. doi:10.1016/j.ccell.2016.02.003.