New CU Boulder study suggests that cancer cells are significantly smarter than previously thought. In just one to two hours, these cells may activate a defense mechanism to withstand an attack from potent new medications called CDK2 inhibitors, which are intended to stop cancer from spreading.
The research, which was released on June 8 in the journal "Cell," does have one positive aspect.
It uncovers how cancer cells complete this adaptation and demonstrates how giving a second, already widely used medicine at the same time may inhibit cancer cells and reduce tumors that are resistant to treatment. The results support the hypothesis that two medications may be more effective than one in the treatment of drug-resistant breast cancer. This hypothesis is presently being investigated in at least three clinical studies.
A potential new area for the treatment of cancer
The trial, a partnership with the pharmaceutical giant Pfizer Inc., is focused on a new class of medications known as CDK inhibitors.
All cells, such as skin or breast tissue cells, go through the cycle of growth, division, and replication thanks to enzymes called cyclin-dependent kinases (CDKs), which include CDK 4, 6, 2, and 1. Scientists think that enzymes 4 and 6 are responsible for kicking off the cycle. Each enzyme has a specific role and position in the process. CDKs can promote the growth of tumors when they are overexpressed or exhibit dysregulation.
Three CDK4 and CDK6 inhibitors (Palbociclib, Ribociclib, and Abemaciclib) have received FDA approval since 2015, including for the most prevalent subtype of breast cancer known as HR+ HER2- (hormone receptor-positive, ERBB2-negative metastatic cancer).
The pharmaceuticals have turned out to be less harmful and more efficient than earlier therapies, catapulting them to blockbuster status with annual global sales in the billions of dollars.
However, some patients do not respond well to them, and many develop resistance. As a result, researchers are now focusing on CDK2, a distinct member of the enzyme family.
Pfizer and Spencer, a leader in time-lapse cell imaging, started working together in 2016 to explore how cancer cells react to their novel CDK2 inhibitor. Over the course of two days, Spencer's laboratory photographed ovarian and breast cancer cells while they were still alive.
A startling finding was made early on.
Initially, the medication reduced CDK2 activity in the cells, but after one to two hours, that activity started to increase.
Spencer said that this was the quickest adaption he had ever witnessed. It was strange.
Even though the first results were disappointing, the researchers kept looking for the root of this rapid "drop-rebound" phenomenon over a period of several years. It functions somewhat analogously to a runner who rejoins a relay race to take the baton from a downed comrade. When the medication rendered CDK2 inactive, CDK4 and CDK6 resumed their role of encouraging cell proliferation.
According to earlier studies, CDK2 steps in to help when CDK4 and CDK6 are destroyed by inhibitors. According to the current research, the opposite is also accurate.
The effectiveness of co-drugs
The team's subsequent research included using CDK2 and CDK4/6 inhibitors to treat tumors in animals as well as cancer cells in petri dishes.
The tumors in both cases stopped growing.
Spencer speculates that CDK4 and CDK6 may be lurking throughout the cell cycle, ready to step in and help when CDK2 is compromised. The team is still investigating why this occurs. According to her, CDK2 inhibitors combined with CDK4/6 inhibitors may one day be utilized to treat breast cancer patients who haven't reacted well to current treatments as well as those who have.
In the team's following studies, tumors in animals and cancer cells in petri dishes were both treated utilizing CDK2 and CDK4/6 inhibitors.
In both cases, the tumors stopped growing.
Spencer makes the speculative claim that CDK4 and CDK6 may be hiding out throughout the cell cycle, ready to intervene and provide support if CDK2 is damaged. The cause of this is currently being looked at by the team. She believes that CDK2 inhibitors and CDK4/6 inhibitors may one day be used to treat both individuals with breast cancer who have responded well to existing therapies as well as those who have not.
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