A combination of two drugs may be more effective in treating resistant breast cancer

Cancer cells are even smarter than scientists once thought, according to new research from the University of Boulder. When these cells are confronted with powerful new drugs called CDK2 inhibitors designed to prevent cancer growth, they can trigger evasions and survive the attack in as little as an hour or two.

However, the study was published in a journal on June 8.cell,” has a silver lining.

The study reveals how cancer cells complete this adaptation, and the simultaneous administration of a second, already widely available drug could impede cancer cells and shrink resistant tumors. It shows that there is a The findings support the idea that two drugs may be better than one when it comes to treating resistant breast cancer, and are currently being studied in at least three clinical trials. .

Our study suggests that combining these new CDK2 inhibitors in clinical development with existing agents may lead to more effective treatments. It also provides a very basic and basic understanding of how the cell cycle is wired for robustness and why so many tumors continue to grow despite drugs to block growth. clarify understanding. ”

Sabrina Spencer, Senior Author, Associate Professor of Chemistry, University of Boulder

A promising new frontier in cancer therapy

The research, conducted in collaboration with pharmaceutical company Pfizer, focuses on a class of new drugs called CDK inhibitors.

Cyclin-dependent kinases (CDKs), including CDKs 4, 6, 2, and 1, are enzymes that guide all cells, including skin and breast tissue cells, through cycles of growth, division, and replication. Each enzyme has its own function and role in the process, and the scientist believes that 4 and 6 start the cycle. Overexpression or dysregulation of CDKs can promote tumorigenesis.

Since 2015, the U.S. Food and Drug Administration has approved three drugs that inhibit CDK4 and 6 (palbociclib, Ribociclib, abemaciclib) were approved. metastatic cancer).
The drug has proven to be less toxic and more effective than previous treatments, propelling it to blockbuster status with billions of dollars in annual global sales.

However, some patients do not respond to them and many develop resistance. This fact prompted researchers to study another member of her enzyme family, CDK2.

In 2016, Pfizer began a research collaboration with Spencer, the world leader in time-lapse cellular imaging, to study how cancer cells respond to its new CDK2 inhibitor. Spencer’s lab took pictures of live ovarian and breast cancer cells every 15 minutes for two days.

A surprising discovery was made early on.

Intracellular CDK2 activity declined sharply upon initial exposure to the drug, but within 1–2 hours it began to recover.

“It was the quickest adaptation we’ve ever seen,” Spencer said. “It was strange.”

Initially, these findings were disappointing, but researchers continued to work for several years to pinpoint the cause of this rapid “drop rebound” effect. This is analogous to a runner re-entering a relay race to pick up the baton from an injured teammate. When the drug disabled her CDK2, CDK4 and CDK6 intervened again to keep the cells growing.

Previous studies have shown that CDK2 helps when inhibitors disrupt CDK4 and CDK6. New research shows that the opposite is also true.

The Power of Joint Pharmacotherapy

In follow-up experiments, the researchers tried treating cancer cells in mouse Petri cells and tumors with both CDK2 and CDK4/6 inhibitors.

In both cases, tumor growth stopped.

The researchers are still investigating why, but Spencer speculates that CDK4 and CDK6 may be lurking in the shadows throughout the cell cycle, ready to intervene and help when CDK2 is impaired. . Combining a CDK2 inhibitor with a CDK4/6 inhibitor could ultimately help breast cancer patients who have either failed to respond adequately to existing drugs, or who have responded well but relapsed, he said. said it could be done.

The study results also reveal how other drugs can be combined for better results.

“Although the mammalian cell cycle is commonly thought to be a well-understood, wired and immutable pathway, our work suggests that the cell cycle is much more flexible than is commonly believed. Yes, indicating multiple adaptive pathways under different conditions,” said Spencer. “This is useful information for companies looking to control the cell cycle to treat disease.”