New technique that makes competition between tumor cells visible may help personalize multiple myeloma treatments

Not all cells of the same cancer are the same. They all have genetic errors that turn them into tumor cells, but these errors are not identical. In every cancer, there are populations of cells with different mutations, and it is important to know each population because one of them can become more dominant and cause the cancer to become resistant to treatment. However, research aimed at understanding the properties of each group of cells in a tumor has progressed very slowly until now.

A study from the H12O-CNIO Hematological Tumor Clinical Research Unit now demonstrates in multiple myeloma cells that a technique based on evolutionary theory is useful for revealing how each cell population responds to different drugs, making the resistant tumor.

The work is published in the journal HémaSphere.

Evolutionary competition within the tumor

A cancer can be seen as an ecosystem in which slightly different cells engage in an evolutionary battle in which the strongest, or those most able to resist treatment, will survive. The technique used by CNIO researcher Larissa Haertle, called clonal competition testing, shows in real time how different tumor populations manage to adapt to each treatment, until a certain population becomes dominant over the others.

It’s a very visual tool; the different cell populations are stained with different colors, cultured together and subjected to the different treatments available. After a while, the color of the population, whose genetic profile allowed them to resist the drug used, seems to dominate the culture.

A very heterogeneous tumor

Understanding the behavior of different cell populations is particularly important in multiple myeloma, a blood cancer that often recurs because it becomes resistant to drugs. Multiple myeloma “is very heterogeneous,” says Haertle. “The same tumor can contain many different genetic alterations, and we need to approach it as if it were many different tumors.”

“Clonal competition allows us to see how each population of cells from the same myeloma reacts to treatments,” she adds. “This allows us to better understand the heterogeneity of each patient than usual methods. And we can see in real time how the cells are growing.”

Better able to survive and multiply

With these trials, researchers studied the KRAS gene, altered in 20% of patients with multiple myeloma. They discovered that two specific KRAS mutations confer an adaptive advantage to the cells carrying them, since in the tests carried out they multiplied more than non-mutated cells.

They also discovered three specific alterations – in other genes – that are only beneficial to tumor cells in the presence of two common drugs to treat multiple myeloma. These treatments therefore give these tumor cells an adaptive advantage.

“When the drugs were applied, all other cells died, but those with these mutations became survivors,” says Haertle.

To prevent the tumor from becoming resistant through this mechanism, the authors suggest taking “breaks” in treatment, or even changing treatment when the aforementioned mutations are detected in patients.

The first author, Haertle, and the senior author, Santiago Barrio, developed this study at the Hematological Tumor Clinical Research Unit H12O-CNIO, led by Joaquín Martínez-López, and at the Department of Internal Medicine II of the University Hospital of Würzburg (Germany). ).