In the relentless battle against cancer, researchers have traditionally focused on inhibiting the processes that cancer cells need to divide rapidly. However, this approach has often led to cancer cells developing workarounds, rendering the treatments ineffective. In a study published in Cancer Discovery, researchers from the Netherlands Cancer Institute take a completely different approach—one that aims to overstimulate and exhaust cancer cells, rather than inhibit them.
First author Matheus dos Santos Dias had to convince some of his colleagues before he could start working on this surprising idea. "We're going against the prevailing view that you can only fight cancer cells by inhibiting them," he explains. "But we had strong evidence that it also works if you overstimulate and exhaust them."
The researcher set out to find a drug that stimulates cancer cells, as well as a partner drug that can then finish the job. By doing so, he wants to upset the balance in cancer cells to the point where they can no longer save themselves. "Compare it to the engine of a racing car: if you crank up the RPM and then turn off the cooling, it's bound to crash. This is exactly what we are trying to do with the drugs."
The team found a drug that acts on the protein PP2A, and a WEE1 inhibitor as the best partner. This combination has shown promising results in experiments with cancer cells and mice with patient tumors, with manageable side effects. Surprisingly, even resistant cells seemed less malignant, growing less quickly or not at all.
"Resistance is a huge problem with existing treatments: cells no longer respond and usually become even more aggressive than they already were. So we also looked at what happens when cells stop responding to our treatment. Surprisingly, resistant cells actually seemed less malignant: they grew less quickly, or not at all," dos Santos Dias adds.
The researchers are now preparing to test this approach in the first clinical studies, with the hope that other labs will also start exploring this "paradoxical approach" to cancer treatment. "Scientifically, the concept is hard to refute," says dos Santos Dias. "I hope that other labs will now also start testing this paradoxical approach, including other drugs as well."