In more than half of the patients with advanced melanoma, a serious type of skin cancer, proliferation of the cancer cells is driven by a mutation in the BRAF gene. These patients benefit from drugs called BRAF inhibitors. The inhibitors are often initially very effective, causing the tumors to shrink. But after a while the tumors will start growing again; the cancer cells have developed resistance against the drugs. But this doesn't necessarily mean the end of the treatment. After a medication pause, in which the patients don't take BRAF inhibitors, the tumors will sometimes again be sensitive to the drugs. This phenomenon is called a 'drug holiday effect'. Physicians have observed this effect in patients in the clinic, but what causes it remained unknown.
Until now. Molecular geneticist prof. dr. René Bernards of the Netherlands Cancer Institute has, together with an international group of colleagues, resolved the mystery of the drug holiday effect in melanoma patients. Their findings are published in the journal Nature as an advanced online publication. Bernards came up with a possible solution to the mystery when he found out why in patients with colon cancer and a BRAF mutation, BRAF inhibitors are seldom effective. They learned that this is caused by activation of the EGFR protein in the cancerous colon cells. This enables the cells to survive in presence of the BRAF inhibitors.
Bernards and his team demonstrated that EGFR protein levels were also elevated in tissue samples of several melanoma patients, even though EGFR levels in the same tumors were low before treatment with BRAF inhibitors. Apparently, melanoma cells can gain resistance against these inhibitors in a similar way as colon cancer cells. But why do melanoma cells loose this resistance mechanism after a therapy pause? Additional research showed that although melanoma cells with high EGFR levels can survive in presence of BRAF inhibitors, EGFR negatively affects their division rate. So, when BRAF inhibitors are present, the resistant cells will have the upper hand in the tumor. But as soon as medication with the inhibitors stops, the cells shake off the EGFR. This will enhance their proliferation, but also make them sensitive for the drugs once again.
When he has to explain his research, Bernards likes to compare the different survival tactics of tumors with different roads on a map. There are usually multiple roads from point A to point B. One of these roads will be of preference, because it is the easiest or fastest. But if this preferred road is blocked, you can simply take an alternative one. Tumors behave in a similar way. In case of melanoma cells with a BRAF mutation, the alternative path they take in presence of BRAF inhibitors is apparently very disadvantageous compared to the preferred road. So as soon as the preferred road is unblocked, they return to their old behavior.