Suppressing SMURF2 Expression in Melanoma Cells Lowers the Threshold for MEK Inhibitor Toxicity

Cancer researchers have discovered how melanoma cells are protected from the class of anticancer drugs known as MEK inhibitors and have suggested a new therapeutic approach to circumvent this problem.

The mitogen-activated protein-kinase (MEK) pathway consisting of the kinases RAF, MEK, and ERK is central to cell proliferation and survival but is deregulated in more than 90% of melanomas. Various MEK inhibitors are currently being evaluated in clinical studies, but so far, results have not been promising.

In a recently reported series of experiments, investigators at the University of Manchester (United Kingdom) used Western blotting, quantitative real-time polymerase chain reaction (qPCR), and RNA interference techniques to study MEK inhibition in vivo in melanoma xenografts in mice and zebrafish.

They reported in the December 17, 2012, online edition of the Journal of the National Cancer Institute that killing of melanoma cells by MEK inhibitors required activation of transforming growth factor beta (TGF-beta) signaling. Melanoma cells resistant to the cytotoxic effects of MEK inhibitors counteracted TGF-beta signaling through overexpression of the E3 ubiquitin ligase SMURF2, which resulted in increased expression of the transcription factors PAX3 (paired box 3) and MITF (microphthalmia-associated transcription factor). This data was confirmed by the analysis of 77 human melanoma samples from various stages for SMURF2 and PAX3 expression.

Results indicated that high MITF expression protected melanoma cells against MEK inhibitor cytotoxicity. Depleting SMURF2 reduced MITF expression and substantially lowered the threshold for MEK inhibitor–induced apoptosis. Moreover, SMURF2 depletion sensitized melanoma cells to the cytotoxic effects of the drug selumetinib, leading to cell death at concentrations approximately 100-fold lower than the concentration required to induce cell death in SMURF2-expressing cells. Mice treated with selumetinib alone at a dosage of 10 mg/kg body weight once daily produced no response, but in combination with SMURF2 depletion, selumetinib suppressed tumor growth by 97.9%.

Senior author Dr. Claudia Wellbrock, a researcher in molecular cancer studies at the University of Manchester, said, "Much of cancer research is now focused on finding new drug combinations. It is recognized that cancers frequently find new ways to combat even the most novel and highly efficient drug treatments, so we are now focusing on targeting the mechanisms that allow the cancer cells to overcome the drug effects. We are very excited about the potential for this new approach that has proved to be so effective in our experiments. If we can reduce the toxicity to all cells, it will mean cancer treatments are less harmful to patients. It is vital that we improve the treatments for melanoma, which is the fifth most common cancer in the UK. By the time many people are diagnosed with melanoma the cancer has already started to spread and advanced tumors can be highly resistant to conventional cancer treatments. The development of resistance to new drugs has also been a major drawback. If we can identify more potent and less toxic drug combinations to tackle melanoma then we could save thousands of lives."

Dr. Wellbrock's research team is now screening drug libraries for existing compounds capable of reducing the activity of SMURF2 in melanoma cells.

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