Cyclin D1/CDK4 inhibitor treatment overcame resistance to targeted therapy in transgenic mouse models, cell cultures, and human tissue samples of human epidermal growth factor receptor 2 (HER2)-positive breast cancer, according to a recent study published in Cell Culture. Researchers examined cyclin D1/CDK4 inhibitors because the cyclin D1/CDK4 complex is a group of proteins that increase cell proliferation and growth.1
HER2 blockers can be effective targeted therapy in HER2-positive breast cancer, but HER2-positive breast cancer frequently develops resistance to targeted therapies, particularly in metastatic tumors. HER2-positive breast tumors carry too many human epidermal growth factor receptor 2.
Researchers used a transgenic mouse model in which they could increase or decrease the production of HER2 protein to determine how resistance occurs. Increased HER2 resulted in humanlike HER2-positive mammary tumors. Decreased HER2 caused the tumors to shrink, though in approximately two-thirds of the mice, tumors recurred.
Researchers examined tissue samples from original and recurrent tumors using RNA sequencing. They discovered that the recurrent tumors had overactive genes involved in cell division and growth, particularly cyclin D1 and CDK4, which can form a progrowth protein complex.
“In HER2-positive breast cancer, cyclin D1 partners with CDK4 to drive cell proliferation,” said Shom Goel, MD, PhD, a medical oncologist at the Susan F. Smith Center for Women’s Cancers at Dana-Farber Cancer Institute, Boston, Massachusetts, and first author of the study.
“We hypothesized that cyclin D1 and CDK4 might also enable tumors to become resistant to HER2-targeted treatments and eventually recur.”
Results from cell cultures and additional mouse experiments suggested that the cyclin D1/CDK4 complex is important in the development of resistance in HER2-positive tumors. The researchers examined abemaciclib, a CDK4 inhibitor, to overcome the resistance. Administration of abemaciclib overcame HER2 inhibitor resistance.
“Finding ways to re-sensitize drug-resistant tumors, to restore their vulnerability to front-line agents, is a critical priority for cancer researchers,” explained Goel.
When researchers added a HER2 inhibitor to abemaciclib, the results were even more pronounced. In addition, abemaciclib administration delayed the recurrence of HER2-positive mammary cancer in mice, as did the administration of both abemaciclib and a HER2 inhibitor, suggesting abemaciclib treatment could help prevent breast cancer recurrence.
“Strikingly, when we added a HER2-targeting drug to abemaciclib, we saw even greater efficacy. This means that abemaciclib restored the cancer cells’ sensitivity to HER2-directed agents,” said Goel.
Clinical trials in the United States and Europe are planned for later this year.
1. Goel S, Wang Q, Watt AC, et al. Overcoming therapeutic resistance in HER2-positive breast cancers with CDK4/6 inhibitors. Cancer Cell. 2016;29(3):255-269. doi:10.1016/j.ccell.2016.02.006.