Tumors resistant to Zelboraf® (vemurafenib) in patients with melanoma showed reduced growth after treatment was stopped. What’s more—animal models have shown that drug resistance was prevented by intermittent treatment. These results were presented at the American Association for Cancer Research (AACR) Annual Meeting 2013, held in Washington, D.C., April 6-10.
Of the more than one million new diagnoses of skin cancer each year, roughly 68,000 involve melanoma. More than 8,000 people die of melanoma each year in the United States. What makes melanoma so dangerous is that it is more likely than other types of skin cancer to spread (metastasize) to other parts of the body.
In order to provide more individualized and more effective cancer therapy, much research has been focused on determining specific pathways involved in cancer cell growth or survival. The BRAF gene is known to play a part in cell growth, and mutations in BRAF are common in several types of cancer. Approximately half of all melanomas carry a specific BRAF mutation known as V600E and in those patients, the nearby MEK pathway is also highly active.
Currently, Zelboraf is the only BRAF inhibitor approved for treating melanoma. Zelboraf has been shown to improve outcomes among patients with advanced melanoma with a BRAF gene mutation, but also accelerates the development of secondary skin cancers in some patients. Furthermore, most patients eventually develop resistance to the drug.
Researchers have investigated the drug resistance mechanism in mice and found that the tumors not only develop a resistance to Zelboraf, but they also become dependent on the drug to grow. Tumors stopped growing and regressed when Zelboraf treatment was stopped in the animals.
In order to determine whether this drug dependency translated from animals to humans, researchers evaluated 42 patients with Zelboraf-resistant tumors at the Royal Marsden Hospital in London, United Kingdom. They examined computed tomography (CT) scans of tumors (available for 19 patients) after treatment was stopped and found that 14 patients experienced a decreased rate of tumor growth.
After determining that the same phenomenon occurs in mice and humans, the researchers implanted mice with human patient-derived tumors and treated them with either continuous or intermittent Zelboraf. Intermittent treatment was delivered for four weeks on and two weeks off. They found that none of the tumors in the intermittent group developed drug resistance.
The researchers concluded that treatment cessation decreased tumor growth in patients with Zelboraf-resistant melanoma and that an intermittent treatment regimen might help overcome drug resistance. Further research is warranted.
 Thakur MD, Fisher R, Salangsang F, et al. Modeling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Presented at the AACR Annual Meeting 2013, held in Washington, D.C., April 6-10. Abstract LB-144.
 Su F, Viros A, Milagre C et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. New England Journal of Medicine. 2012;366:207-15.
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