New research into melanoma reveals that drug-resistant tumours often become drug-dependent. Amazingly, removal of the drug triggers a second wave of remission, offering a novel, cost-effective way to treat advanced cancer.
Metastatic melanoma is an aggressive and deadly skin cancer. While up to 50% of patients can benefit from Roche’s new drug vemurafenib, the majority of these patients relapse with a drug-resistant form of the disease within six months. Efforts to tackle this problem led to a partnership between Novartis and the University of California, San Francisco (UCSF), that has uncovered a surprising strategy against vemurafenib-resistant melanoma: simply remove the drug!
This may seem counterintuitive, and to see why it works we have to understand a bit about how cancer cells modify their existing machinery to survive drug treatment. A group of enzymes in our cells, collectively known as the BRAF/ERK pathway, respond to cues outside the cell and turn them into signals that tell the cell to stay alive and divide. The inability to switch off these signals, a result of genetic mutations in the enzymes themselves, causes uncontrolled cell division, the root cause of cancer. Vemurafenib inhibits the mutated form of the enzyme BRAF; this blocks ERK signals and forces mutant cells to die. While the vast majority of tumour cells respond in this way, a tiny subset are still able to amplify the mutated BRAF, squeezing out enough ERK signals to carry them through the vemurafenib blockade. This population expands to create new, drug-resistant tumours.
The fact that BRAF is amplified to drive resistance explains why removal of the drug kills drug-resistant cells. This is because cells can sense not just the presence of ERK signals, but also the quantity of them, a concept introduced as far back as the mid-nineties. Too few ERK signals, and cells cannot survive; too many, and cells stop dividing and differentiate or die. This ‘Goldilocks’ phenomenon, where ERK signalling has to be ‘just right’, evolved both to promote and restrict cell division during normal tissue development, and was seized upon by Dr Meghna Das Thakur and colleagues at Novartis and UCSF. In a recent paper published in Nature, they show that when human vemurafenib-resistant tumours (transplanted into mice) were denied the drug, the amplified BRAF that had previously maintained ERK levels then sent them into overdrive. The tumour cells, sensing that ERK signalling was now ‘too high’, promptly died. Of course, conversely to the initial resistance mechanism, a subset of these cells were able to downregulate their BRAF/ERK pathway and avoid death. New tumours subsequently arose, but these were now composed of ‘BRAF-low’ cells that were sensitive to vemurafenib.
In this study repeated cycles of vemurafenib treatment and withdrawal resulted in the survival of all mice tested, whereas in those undergoing continuous vemurafenib treatment survival was around 25%. While this style of ‘on-off’ therapy is yet to be trailed in humans, retrospective analysis of patient data suggests many patients who stopped taking the drug subsequently survived longer than predicted. Intriguingly, the same phenomenon in other cancers may allow such strategies to be used more generally in our on-going battle against this most dreaded human disease.
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