CDK11B: A Druggable Vulnerability in Breast Cancer
Abstract
Breast cancer cells require the expression of certain genes in order to grow. These genes, called “addictions” or “dependencies,” are promising drug targets because blocking the function of a breast cancer dependency can lead to cancer cell death. For instance, certain breast cancers are addicted to the expression of the Her2 protein, and drugs that target Her2 are highly effective at blocking cancer growth in these patients. Cyclin-dependent kinases (CDKs) are a family of proteins that play multiple roles in cancer biology. Two cyclin-dependent kinases, called CDK4 and CDK6, are known to be dependencies in some breast cancers. A drug that blocks CDK4 and CDK6, called Ibrance, nearly doubles progression-free survival when given to these patients. Unfortunately, many tumors eventually come back after treatment with this drug, and some patients receive no benefit at all from taking it. Nonetheless, the overall success of Ibrance demonstrates that cyclin-dependent kinases are important breast cancer drug targets. It may be the case that targeting other members of this family could also provide a significant therapeutic benefit to breast cancer patients. We have recently discovered that a poorly characterized cyclin-dependent kinase, called CDK11B, is a novel breast cancer dependency. Additionally, we found a drug that kills breast cancer cells by blocking CDK11B’s function. We are excited by the possibility that CDK11B inhibition could be a new and highly effective strategy to treat breast cancer patients. The overall goal of this project is to learn more about CDK11B’s function in breast cancer and to test whether CDK11B inhibition can be safely used to treat breast cancer in mice. To accomplish this, we will assess the effects of blocking CDK11B in a wide range of breast cancer cells, so that we can determine whether a particular type of breast cancer is particularly sensitive to this drug. Additionally, with any new therapy, it is very important to determine whether it will cause toxic side effects. As a first step in this determination, we will study how mice respond when they are treated with the CDK11B inhibitor: if they lose weight and become sickly, then it may indicate that this drug is too toxic for human use. However, if the drug is capable of blocking breast cancer growth in mice without causing many side effects, then this would provide one line of evidence suggesting that it may be safe to try in people. If we are satisfied with the performance of this drug in mice, then this may lead to additional studies in the future to confirm its low toxicity in larger mammals. If these experiments also yield favorable results, then clinical trials in human breast cancer patients could begin in one to 2 years. Alternately, these experiments may suggest to us that the drug that we have found can be improved. In that case, we would make minor chemical modifications to it in order to maximize its potency and minimize its toxicity. This new drug could then be taken into clinical trials in 3 to 4 years. These careful studies in breast cancer cell lines and in mice are necessary to confirm that a drug is safe and effective before it is tested in vulnerable cancer patients. Nonetheless, we are very excited by the possibility that CDK11B inhibitors will save the lives of individuals with breast cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010680
Entities
People
- Jason Sheltzer
Organizations
- Cold Spring Harbor Laboratory
- United States Army