Why an anticancer drug has “off-target” effects
Researchers discover why about a fifth of melanoma patients treated with vemurafenib go on to develop another type of skin cancer.
Over 50% of melanomas — a highly lethal form of skin cancer — carry mutations in a gene called BRAF. The BRAF gene encodes an enzyme that helps to regulate the proliferation of cells, but mutations in this gene lead to the excessive proliferation that is seen in cancer. Clinical trials have shown that a drug called vemurafenib can be used to treat patients who carry the mutated BRAF genes and go on to develop melanoma, but around one fifth of these patients developed another type of skin cancer called cSCC (which is short for “cutaneous squamous cell carcinoma”).
The cSCC tumors often develop in areas where the sun has damaged the patient’s skin. It is thought that their growth is then accelerated by vemurafenib activating another enzyme, ERK, which causes the excessive proliferation of skin cells. Harina Vin, Sandra Ojeda, Grace Ching and co-workers have now found that vemurafenib might also cause cSCC tumors by blocking another signaling pathway. The experiments were performed in human cells and also in mice, and the results were then verified in human cSCC samples.
Cells that are exposed to UV radiation usually die, but when treated with vemurafenib, some 70% of the cells that would have died instead survived. The stress from the UV radiation activates the JNK signaling pathway, which causes the irradiated cells to die. However, Vin, Ojeda, Ching and co-workers found that cSCC cells had very low levels of JNK signaling because treatment with vemurafenib had the unintended effect of inhibiting three enzymes that are needed to fully activate the JNK signaling pathway.
Vin, Ojeda, Ching and co-workers estimate that suppression of JNK signaling and cell death is responsible for about 17.6 to 40% of the effect on cSCC growth seen in melanoma patients, with activation of the ERK pathway accounting for the rest. These unexpected findings suggest that combining vemurafenib treatment with radiation or chemotherapy should be done with caution as these effects could affect their efficacy. It also suggests that future drugs should be designed in a way that avoids these types of effects by making sure they do not inhibit important ‘off-target’ enzymes.
To find out more
Read the eLife research paper on which this story is based: “BRAF inhibitors suppress apoptosis through off-target inhibition of JNK signaling” (November 5, 2013).
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