In a groundbreaking revelation, recent research conducted at CU Boulder has exposed cancer cells’ remarkable ingenuity, surpassing previous scientific understanding. The study’s findings demonstrate that when confronted with potent CDK2 inhibitors, a new class of drugs designed to impede cancer proliferation, cancer cells can swiftly activate alternative mechanisms to survive the attack within a mere one to two hours.
However, amidst these disconcerting revelations, a glimmer of hope emerges.
The research elucidates how cancer cells execute this adaptation process and unveils a potential solution: simultaneously administering a second, already available drug could cripple cancer cells and shrink resistant tumors. These findings fortify the notion, currently being investigated in multiple clinical trials, that when combating treatment-resistant breast cancer, a combination of two drugs may yield superior results compared to a single agent.
“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. 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,” asserts Sabrina Spencer, senior author and associate professor of biochemistry at CU Boulder.
Pioneering Cancer Treatment on the Horizon This study, conducted in collaboration with pharmaceutical company Pfizer Inc., revolves around a novel class of drugs called CDK inhibitors.
Cyclin-dependent kinases (CDKs), including CDK 4, 6, 2, and 1, are enzymes that guide all cells, such as skin or breast tissue cells, through the cycle of growth, division, and replication. Each enzyme plays a distinct role in the process, and scientists believe that CDK 4 and 6 initiate the cycle. Dysregulation or overexpression of CDKs can drive tumor formation.
Since 2015, the U.S. Food and Drug Administration has approved three drugs targeting CDK4 and 6 inhibition (Palbociclib, Ribociclib, and Abemaciclib), including for the most prevalent subtype of breast cancer, known as HR+ HER2- (hormone receptor-positive, ERBB2-negative metastatic cancer). These drugs have proven to be less toxic and more effective than previous treatments, attaining blockbuster status with billions of dollars in global sales each year.
Nonetheless, a subset of patients fails to respond to these drugs, and many eventually develop resistance, leading researchers to explore alternative targets within the CDK family, such as CDK2.
In 2016, Pfizer embarked on a collaboration with Spencer, an eminent expert in time-lapse cell imaging, to investigate how cancer cells respond to their CDK2 inhibitor. Spencer’s laboratory captured images of living ovarian and breast cancer cells every 15 minutes over a two-day period.
Early on, a surprising revelation emerged.
While CDK2 activity plummeted in the cells upon initial exposure to the drug, it rebounded within one to two hours.
“This was the fastest adaptation we had ever seen,” commented Spencer. “It was bizarre.”
Although these findings initially proved disheartening, the researchers persevered for several years to unravel the underlying cause behind this rapid “drop-rebound” effect. The phenomenon resembles a runner re-entering a relay race to retrieve the baton from an injured teammate. When the drug incapacitated CDK2, CDK4 and CDK6 stepped in to prod the cells to proliferate.
Previous research had shown that when CDK4 and CDK6 were inhibited, CDK2 would come to the rescue. The current study now reveals that the reverse is also true.
The Power of Combination Therapy In subsequent experiments, the team administered CDK2 and CDK4/6 inhibitors to cancer cells cultured in petri dishes and tumors in mice.
In both cases, the tumors ceased to grow.
While the precise mechanisms behind this phenomenon are still being explored, Spencer hypothesizes that CDK4 and CDK6 may linger in the background throughout the cell cycle, ready to intervene when CDK2 is impaired. She suggests that combining CDK2 inhibitors with CDK4/6 inhibitors could be employed to assist breast cancer patients who have not responded well to existing drugs or those who initially responded positively but relapsed.
These findings also shed light on the potential for combining other drugs to achieve enhanced therapeutic outcomes.
“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,” explains Spencer. “That’s useful information for any company trying to drug the cell cycle to treat disease.”
As cancer cells continue to unveil their strategies, researchers push forward, harnessing new knowledge to outsmart these formidable adversaries. The quest to conquer cancer rages on, driven by groundbreaking discoveries and the hope of delivering more effective treatments to those in need.