The protein kinases Cdk4 and Cdk6 may determine the incidence and aggressiveness of leukemia, according to preclinical research.
The study showed that Cdk4 and Cdk6 cooperate to promote hematopoietic tumor development in mice.
And inhibiting Cdk4 and Cdk6 simultaneously proved a more effective method of fighting leukemia than inhibiting either protein alone.
The researchers recounted these findings in Blood.
“Cdk4/6 inhibitors used in cancer treatment don’t differentiate between the two molecules,” said study author Marcos Malumbres, PhD, of the Spanish National Cancer Research Centre (CNIO).
“The effectiveness of blocking both proteins at once has not been demonstrated to date.”
To get a wider perspective on this issue, Dr Malumbres and his colleagues designed genetically modified mice carrying active Cdk4, active Cdk6, or both versions of the active proteins.
The researchers found that simultaneous activation of both proteins promoted tumor growth in the mice, leading to more aggressive tumors and an increased risk of developing leukemia.
The team also found an explanation for why the simultaneous activation of Cdk4 and Cdk6 leads to such aggressive tumors.
Under normal conditions, Cdk4 and Cdk6 are inhibited by p16INK4A proteins. But when both Cdk4 and Cdk6 are present at high levels, p16INK4A proteins are unable to act as a retaining wall, leading to uncontrolled tumor growth.
“The assumption to date has been that these molecules act independently of each other,” Dr Malumbres said. “However, our recent findings now suggest that the combined inhibitors could be a more effective cancer treatment.”
“The clinical success of these compounds depends on the appropriate selection of patients. Our findings could help us to understand the molecular basis underpinning the success of these inhibitors, thereby contributing to the development of novel and more effective drugs.”
