For the first time, researchers have observed the mechanism by which cancer cells resist the effects of chemotherapy. The findings could be used to develop targeted drugs to help overcome this mechanism and make chemotherapy more effective. When cells divide, tiny tube-like structures called microtubules within the cell act like mechanical arms, pulling genetic material apart and ensuring the successful creation of daughter cells. Cancer cells divide at a faster rate than normal cells, so antimicrotubule chemotherapy drugs target these structures to inhibit cancer cell growth.
But cancer cells are so cunning that they have developed ways to ensure that treatments don't always work. Now, UNSW Sydney researchers have observed for the first time a mechanism by which cancer cells resist the effects of chemotherapy.
Peter Gunning, the study's corresponding author, said: "Anti-microtubule chemotherapy often breaks the robotic arms into multiple hubs, pulling chromosomes in multiple directions instead of the normal two. The resulting chaos blocks the normal separation of chromosomes into the two daughter cells and induces apoptosis, or programmed cell death."
Researchers have discovered that cancer cells use a clever technique to continue dividing and avoid the effects of chemotherapy.
"We found that cancer cells use the mechanical forces provided by the cell edge, called the cell cortex, to overcome the effects of commonly used chemotherapy, which hinders the cell's ability to separate chromosomes during division," Gunning said.
When microtubules break, cancer cells activate a signal that causes the "arms" to extend toward the edge of the cell, pulling the cell cortex and reuniting the broken microtubules. This allows the arms to stabilize and generate the necessary force to physically grab the chromosomes and pull them into each daughter cell, ensuring the proliferation of cancer cells.
Researchers suspected the existence of this mechanism after noticing that a specific microtubule-targeting drug used to treat neuroblastoma, a childhood cancer, enhanced the effects of chemotherapy. However, in their previous studies, imaging technology was not advanced enough to confirm their suspicions.
"We need good imaging of cancer cells as they divide, so we can see in real time what changes are happening to chromosomes, microtubules and cell structure," Gunning said. "This was quite surprising to us because we didn't expect this mechanism of cancer cells to be used in this way to overcome cancer therapies, but we can see it happening before our eyes."
High-dose chemotherapy is often effective in stopping cancer cells from dividing. However, at lower doses—for example, when a patient develops chemotherapy toxicity and needs to reduce the dose—the cells can take advantage of this innate survival mechanism, which researchers believe is a fundamental part of cell biology.
"We think this is a backup mechanism that evolved to allow any cell to overcome small amounts of microtubule disruption and ensure its survival. It just so happens that cancer cells use it to avoid anti-microtubule chemotherapy," Gunning said.
Researchers are working to develop drugs that can be used in combination with current chemotherapy drugs to turn off resistance mechanisms.
"By attacking the force-generating mechanisms established by cancer cells, we hope to make cancer therapies work more effectively," Gunning said. "We have actually founded a company that can develop the drugs needed to attack this rescue mechanism, allowing anti-microtubule chemotherapy to work more effectively and hopefully improve patient outcomes."
The research was published in the journal Current Biology.