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When it comes to treating resistant breast cancer, 2 drugs may be better than 1

When it comes to treating resistant breast cancer, 2 drugs may be better than 1

Cancer cells are even smarter than scientists previously believed, according to new 麻豆免费版下载Boulder research. When these cells are confronted with potent new drugs called CDK2 inhibitors, which are designed to prevent cancer from proliferating, they can trigger a workaround to survive the assault in as little as one to two hours. 

But the study,  comes with a silver lining. 

It reveals how cancer cells complete this adaption and shows that simultaneously administering a second, already widely available drug may hobble cancer cells and shrink resistant tumors. The findings bolster the idea, which is currently under investigation in at least three clinical trials, that when it comes to treating resistant breast cancer, two drugs may be better than one.

鈥淥ur research suggests that you can potentially have a more effective treatment by combining these new CDK2 inhibitors in clinical development with a drug that already exists,鈥 said senior author Sabrina Spencer, associate professor of biochemistry at 麻豆免费版下载Boulder.

鈥淚t also uncovers a very basic, fundamental understanding about how the cell cycle is wired for robustness and why so many tumors manage to proliferate in the face of drugs meant to block proliferation.鈥

A promising new frontier in cancer treatment

Sabrina Spencer headshot

Sabrina Spencer

The study, a collaboration with pharmaceutical company Pfizer Inc., centers around a class of new drugs called CDK inhibitors.

Cyclin-dependent kinases (CDKs), including CDK 4, 6, 2 and 1, are enzymes that usher all cells, such as skin or breast tissue cells, through the cycle of growth, division and replication. Each of the enzymes has its own function and place in the process, and scientists believe that 4 and 6 kick-start the cycle. When CDKs become overexpressed or dysregulated, they can drive tumor formation.

Since 2015, the U.S. Food and Drug Administration has approved three drugs to inhibit CDK4 and 6 (Palbociclib, Ribociclib and Abemaciclib), including for the most common subtype of breast cancer, known as HR+ HER2- (hormone receptor-positive, ERBB2-negative metastatic cancer).

The drugs have proven less toxic and more effective than previous treatments, propelling them to blockbuster status with billions of dollars in annual global sales.

But some patients don鈥檛 respond to them and many develop resistance, a fact that has prompted researchers to go after a different member of the enzyme family鈥擟DK2.

In 2016, Pfizer began collaborating with Spencer, a global leader in time-lapse cell imaging and member of the 麻豆免费版下载Cancer Center, to study how cancer cells respond to their new CDK2 inhibitor. Spencer鈥檚 lab took pictures of living ovarian and breast cancer cells every 15 minutes over the course of two days.

Early on, a surprising discovery emerged.

While CDK2 activity plummeted in the cells upon initial exposure to the drug, within one to two hours, that activity began rebounding. 

鈥淭his was the fastest adaptation we had ever seen,鈥 said Spencer. 鈥淚t was bizarre.鈥

While those findings were, initially, disappointing, the researchers continued their research for multiple years to determine what was causing this swift 鈥渄rop-rebound鈥 effect. It works a bit like a runner who re-enters a relay race to grab the baton from an injured teammate. When the drug disabled CDK2, CDK4 and CDK6 stepped back in to continue prodding the cells to proliferate.

Previous research has shown that when inhibitors take out CDK4 and CDK6, CDK2 comes to the rescue. The new study shows that the reverse is also true.

The power of co-drugging

In follow-up experiments, the team tried drugging cancer cells in petri dishes and tumors in mice with both CDK2 and CDK4/6 inhibitors.

In both cases, the tumors stopped growing.

The team is still exploring why that happens, but Spencer suspects that CDK4 and CDK6 may stand in the shadows throughout the cell cycle, ready to jump in and assist when CDK2 is impaired. She said CDK2 inhibitors in combination with CDK4/6 inhibitors could, ultimately, be used to help breast cancer patients that haven鈥檛 responded well to existing drugs, as well as those who responded well but then relapsed.

The findings also shed light on how other drugs could be combined for better results. 

鈥淭he mammalian cell cycle is commonly conceived as a well-understood, hardwired, invariant pathway, but our work indicates that the cell cycle is much more plastic than generally believed, with multiple adaptive routes under different conditions,鈥 said Spencer. 鈥淭hat鈥檚 useful information for any company trying to drug the cell cycle to treat disease.鈥