CDK4/6 Inhibitors May Play Role in Triple-Negative Breast Cancer Metastasis

A study recently published is suggesting that a key drug target, CDK4/6, regulates a cancer metastasis protein, and may play a role in combating metastasis in triple-negative breast cancer. In addition, this new finding may point to a new way of preventing metastasis in other cancers.

Investigators at the Mayo Clinic are reporting in Nature Communications that CDK4/6-dependent activation of DUB3 regulates cancer metastasis through SNAIL1. They theorize that the CDK4/6–DUB3 axis may be an important regulatory mechanism of breast cancer metastasis. They write that findings with several xenograft models are providing a rationale for potential therapeutic interventions in the treatment of breast cancer metastasis.

CDK4/6 inhibitors are approved for treating estrogen-positive breast cancer, but not triple-negative breast cancer. Currently, triple-negative breast cancer is difficult to treat because it does not exhibit receptors for estrogen, progesterone, or the HER-2/neu gene, which are targets for many breast cancer treatments.

Study senior author Zhenkun Lou, PhD, of the Mayo Clinic, Rochester, Minn., said prior published data suggested that CDK 4/6 inhibitors were not effective in reducing estrogen receptor-negative breast cancer growth rates. In this study, the team demonstrated that inhibition of CDK4/6 blocks breast tumor metastasis in a triple-negative breast cancer model. However, it accomplished this without affecting tumor growth.

“Our data confirmed that, while the rate of growth of triple-negative breast cancer was not affected by CDK 4/6 inhibitors, this class of drugs was able to significantly inhibit the spread of triple-negative breast cancer to distant organs when tested in multiple different triple-negative breast cancer models, including patient-derived xenografts,” said Lou.

PD0332991 (palbociclib) is a potent anti-proliferative agent in multiple cancer cells and an inhibitor of CDK4/6, according to the researchers.  The study showed in human triple-negative breast cancer samples that PD0332991 does not affect the growth of the primary tumor. However, the researchers found in xenograft models (from a breast cancer patient and a TNBC cell line) that PD0332991 induced the inactivation of DUB3 and the destabilization of the SNAIL1 protein.  PD0332991 also decreased cell migration, according to the study.

Lou cautioned that more research is necessary. However, if these new findings are corroborated, they could significantly expand the use of CDK 4/6 inhibitors for the prevention of metastasis prevention in other cancers that exhibit a high level of the SNAIL protein. Currently, researchers at the Mayo Clinic are designing new studies that will focus on the role of CDK 4/6 inhibitors and their potential to inhibit cancer metastasis in women with triple-negative breast cancer who are at highest risk for advanced disease.