Resistance to chemotherapy is a major killer, and new work explains why it happens for one widely used chemotherapy drug. Eventually, this could lead to a method for preventing this resistance, transforming the fight against several cancers, including two of the most common ones. More immediately, however, it could identify cases where resistance is likely to occur, offering an opportunity to use alternative treatments.
5-Fluorouracil (5-FU) is the most used chemotherapy against breast, colorectal, and several rarer cancers, saving enormous numbers of lives in the process. Nevertheless, sometimes cancers develop resistance to it, making the treatment ineffective and the prognosis grim. The reasons for this have not been understood.
Dr Hamsa Puthalakath of La Trobe University compared cancers that resist 5-FU to those that don't. In Proceedings of the National Academy of Sciences, he attributes the difference to a protein called BOK, previously regarded as fulfilling a role similar proteins perform better.
“I have always believed that nature keeps proteins for a reason,” Puthalakath said in a statement. “Our research shows BOK binds with an enzyme called UMPS, enhancing cells’ ability to proliferate. Without BOK, cells struggle to synthesize DNA, and they can’t proliferate.” Through the same process, BOK converts 5-FU, an otherwise relatively impotent drug, into the form that kills cells.
Some cancers manage to turn BOK off, leaving 5-FU in its ineffective form and keeping them safe. Since without BOK, UMPS is 3-5 times less effective, this also slows down the cancer's proliferation, but its only a temporary reprieve. Unfortunately, Puthalakath told IFLScience, if cancers survive long enough, they may develop P-53 mutations, which makes them almost invincible. If they then turn BOK back on, there is little we can do to stop them.
The obvious response to this might be to administer BOK with 5-FU, but Puthalakath told IFLScience this is unlikely to be the answer. One option might be to convert 5-FU to its active form before administration, which Puthalakath says is possible but much more expensive.
Instead, Puthalakath is working to find a drug that replicates BOK's role in 5-FU conversion, but cancers cannot turn off so easily. Like all new drugs, however, that means years of experiments on cultured cells, followed by animal and then clinical trials.
There is a way Puthalakath's work could start saving lives much more quickly. Puthalakath said it should be a relatively easy matter to create a test for the presence of BOK that identifies the chance of cancer resistance occurring. Where this is high, 5-FU could be replaced by an alternative chemotherapy. 5-FU is currently preferred because, bad as its side-effects are, the alternative is worse, but greater side-effects are better than not working at all.