Drug resistance: maybe it is only because we have worked too much!

       

        People are no strangers to drug resistance of microbes: Bacteria and viruses cannot be killed by a certain amount of antibiotics which used to work miraculously. Unfortunately, drug resistance is not only limited to microbes but also occurs frequently in cancer cells exposed to drugs each of which targets a few dysfunctional genes in tumors. Such effective targeted anti-cancer drugs often lose its momentum after 6 or 12 month of usage. It seems that the tiny pathogen or tumor cells outsmart the human brain at almost every turn.

        Cancer cells with specific mutations that are targeted by drugs develop drug resistance by producing new mutations that cannot be targeted by drugs any more. Thus, designing new drugs that can target new mutations of cancer cells sounds to be the only way to overcome drug resistance. However, these new drugs will also encounter drug resistance due to the emergence of even more mutations. The scenario is the harder researchers work, the harder and smarter cancer cells work because they want to survive. Can we be smarter to figure out how to conquer drug resistance?  

       Here is the good news: a very simple method, discontinuous drug administration, may be a powerful weapon to help us defeat drug resistance. The so-called discontinuous drug application contains three steps: drug administration, pause of drug administration, and another round of drug administration. Depending on the specific situation of patients, this cycle of drug usage can be repeated or not. Although this strategy seems to be too simple to work, it is in fact working wonderfully.

        A latest paper published in Nature showed the effectiveness of discontinuous drug administration. Frequent mutations in a gene BRAF have been linked to melanoma, a notorious malignant skin tumor. A drug named Vemurafenib can target BRAF to inhibit melanoma. However, long term use of Vemurafenib can lead to drug resistance. Researchers showed that discontinuous dosing of Vemurafenib resulted in effective regression (healing) from drug-resistant tumors. The explanation is as follows: while the survived tumors develop drug resistance, they also become dependent on the drug exposure environment. By discontinuing the drug temporarily, tumors that have established drug resistance will regain the sensitivity to the drug.

        It is of great interest to see whether the discontinuous strategy works on other targeted therapies as well.  If this is proven true, patients will spend less money and suffer less pain in cancer therapy. Scientists will find their lives easier, too.

[1] Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Nature(2013) doi:10.1038/nature11814