Two Drugs May Be Better Than One for Resistant Breast Cancers
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A new study has demonstrated how breast cancer cells can rapidly become resistant to a drug designed to stop them from dividing and also suggests that a combination of drugs may help to treat these resistant tumors. The research is published in Cell.
CDK inhibitor success is marred by resistance
The study, a collaboration between the University of Colorado Boulder (UC Boulder) and Pfizer, focuses on a type of cancer drug that inhibits an enzyme called cyclin-dependent kinase 2 (CDK2).
CDKs help cells to progress through the cell cycle, a multi-step pathway that prepares cells to divide and proliferate. They come in several different forms – CDK4 and CDK6 are of particular importance as they are thought to kick-start the cell cycle. However, CDKs can also drive tumor formation if they go awry or are overexpressed.
Drugs that inhibit CDKs have seen huge success in the treatment of certain types of breast cancers. However, some patients’ tumors do not respond to these drugs, and other patients that previously responded can develop resistance over time. This has inspired researchers to target other CDKs – namely CDK2 – to overcome some of the problems caused by resistance.
The current study – led by Dr. Sabrina Spencer, associate professor of biochemistry at UC Boulder – describes how breast cancer adapts to CDK2, and shows that administering other existing drugs at the same time can help to shrink resistant tumors.
Spencer, an expert in time-lapse cell imaging, and colleagues studied how ovarian and breast cancer cells responded to the Pfizer-developed CDK2 inhibitor PF-06873600.
The team captured images of the drug-treated cells every 15 minutes over the course of 2 days. The images proved surprising, revealing that despite an initial drop in CDK2 activity after dosing with the inhibitor, CDK2 activity showed a resurgence and rebounded within one to two hours.
“This was the fastest adaptation we had ever seen,” said Spencer. “It was bizarre.”
Persevering with the study after their initial disappointment, the researchers next investigated how these cells achieved this astonishing rebound. They found that after CDK2 is disabled, CDK4 and 6 quickly activate, coming to the rescue and encouraging the cells to proliferate. Interestingly, previous research had already shown that CDK2 is activated in response to CDK4 and 6 inhibition – now, these findings reveal that the reverse is also true.
Armed with this information, the researchers carried out follow-up experiments to drug lab-grown cancer cells with inhibitors for CDK2 and CDK4/6, which successfully stopped the cancer cells from growing.
“Our 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,” said Spencer. “It 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.”
Drug combinations hold promise
The research team is still investigating why this effect occurs, though Spencer hypothesizes that CDK4 and 6 may wait in the wings to support CDK2 should it become impaired.
Overall, the study suggests that combining new CDK2 inhibitors with CDK4/6 inhibitors – such as palbociclib, ribociclib and abemaciclib – could be effective for patients with either intrinsic or acquired resistance.
“The 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,” said Spencer. “That’s useful information for any company trying to drug the cell cycle to treat disease.”
Reference: Arora M, Moser J, Hoffman TE, et al. Rapid adaptation to CDK2 inhibition exposes intrinsic cell-cycle plasticity. Cell. 2023;186(12):2628-2643.e21. doi: 10.1016/j.cell.2023.05.013
This article is a rework of a press release issued by UC Boulder. Material has been edited for length and content.