Source Harvard Medical School

The findings of a new Harvard Medical School study suggest important differences between three frontline drugs used to treat advanced breast cancer. The researcher’s findings were published in Cell Chemical Biology.

The three CDK4/6 inhibitors, abemaciclib, palbociclib, and ribociclib have exhibited exceptional efficacy in hindering breast tumor growth, improving survival rates and prompting FDA approval. Currently, all three are utilized as frontline therapies for patients with advanced, HR+/HER2- breast cancers. Although these drugs possess similar biological targets and are often used interchangeably, evidence supports that also display notable differences.

“Despite the sophistication of industrial drug discovery, the activities of many drugs are not fully understood at the time of their approval by the FDA,” said senior study author Peter Sorger, the HMS Otto Krayer Professor of Systems Pharmacology in the HMS Department of Systems Biology and director of the Laboratory of Systems Pharmacology in a press release detailing the study. “In this case, it appears that the drug abemaciclib may unexpectedly work in patients who are not responsive to other drugs in the class.”

One Drug Has Hit A ‘Sweet Spot’

The researchers tested 35 different breast cancer cell lines, and following analysis, uncovered a key difference in the drugs’ biological activity. Although all three inhibitors prevented the growth of cancer cells, the results showed that only abemaciclib caused significant cell death, indicating the drug may be affecting proteins other than CDK4/6. “Whether by accident or design, abemaciclib appears to have hit a sweet spot where it is more efficacious in some regards than the other CDK4/6 inhibitors, but potentially less toxic than earlier pan-CDK inhibitors,” said study co-author Kartik Subramanian, HMS postdoctoral fellow in the Laboratory of Systems Pharmacology. Further animal-model tests with human breast cancer tumors confirmed these observations. The study also found that even in higher doses, palbociclib and ribociclib had minimal effects on cancer cell death.

According to the authors, these results suggest that abemaciclib may have additional therapeutic benefits for a subset of tumors that remain unresponsive to treatment or have grown resistant to other CDK4/6 inhibitors. The study found that even in higher doses, palbociclib and ribociclib had minimal effects on cancer cell death.

The authors caution about these results, noting that their study was based on preclinical, laboratory-based experiments, and that findings remain inconclusive. Rather, they believe their data lay the foundation for conducting clinical studies that will thoroughly assess optimal strategies for CDK4/6 inhibitor treatment.

“Our findings are an important reminder that just because drugs are marketed to have the same nominal targets, it doesn’t mean they are necessarily equally effective in all situations,” said Caitlin Mills, study co-author, and Termeer Fellow. “The most common form of breast cancer is hormone receptor positive, and for CDK4/6 inhibitors, there is the potential to make an enormous difference for a very large number of women by understanding how these drugs could be optimally used.”

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