In recent years, a number of completely new anti-cancer drugs have become available, some of which show clinical activity to cancer types that used to be refractory to treatment. These new drugs belong to the so-called targeted therapies or personalized medicines. With personalized medicine, tumors are no longer treated based on the affected organ. Instead, the focus is put on determining which DNA mutations in the cells have caused them to become cancerous. Then drugs are developed to counter these mutations. Half of the patients with melanoma, an aggressive form of skin cancer, have tumors carrying a mutation in a gene called BRAF. Patients with stage IV melanoma, for whom until recently few treatment options were available, can (if they have the BRAF mutation) benefit significantly from inhibitors targeting mutant BRAF.
Unfortunately, almost all melanomas eventually develop resistance against this drug and patients succumb to the disease. On average, BRAF inhibitors are effective for seven months. If they are administered as a combination therapy with a related drug, called a MEK inhibitor, it takes about twice as long before the tumors stop responding to the drugs. The problem is that melanomas commonly find an 'escape route'. The team of NKI researcher Daniel Peeper has now unraveled one such escape route or resistance mechanism. It turns out that melanoma cells can escape from BRAF inhibitors by shutting down the production of a protein called MITF. This leads to a number of changes in the cancer cells, which eventually causes them to lose their dependency on the BRAF-route to survive. Thus, BRAF-inhibitors become obsolete. Downregulation of their MITF production causes melanoma cells to develop resistance against different types of personalized medicines, including MEK inhibitors.
On top of this, Judith Müller, a postdoc in the group of Peeper, discovered that patients who respond to BRAF inhibitors only briefly or even not at all (this is the case in ten to fifteen percent of the patients), already have much lower MITF expression levels before they start taking the drugs. This is an important indication as to why some patients don't respond to the inhibitors. Peeper: "With MITF, we now have an important biomarker that might predict how patients will respond to this type of therapy."
Preventing this resistance mechanism is challenging. Administering more MITF to the tumors is no option. Technical difficulties aside, it is well established that high levels of MITF also lead to drug resistance. Peeper: "Our research has revealed that melanomas can adapt their MITF levels quite easily, to become drug resistant. Therefore, instead of focusing on adjusting MITF levels, we looked for a different solution." To this end, Müller studied the effect of low MITF levels in melanoma cells. She discovered that this triggers a signal to increase the production of yet another protein, AXL. And the good news is: this protein (a receptor tyrosine kinase) can be inhibited. AXL inhibitors have already been developed, and are currently being evaluated in clinical trials for other types of cancer.
Peeper: "Eventually, we would like to develop a clinical trial in which we treat melanoma patients with an AXL inhibitor. As a combination therapy, together with the BRAF and MEK inhibitors, or perhaps even together with immunotherapy. In doing so we make an attempt to cut off as many known escape routes of the tumor as possible, right from the start. Currently, we are discussing the possibilities of such a trial with a pharmaceutical partner." Further study will be required to determine whether AXL inhibitors indeed represent an effective solution for this newly uncovered resistance mechanism. It is not yet known if and when a clinical trial will take place.