PHILADELPHIA (October 23, 2017) – Fox Chase Cancer Center researchers have discovered a new family of micro-RNAs that disrupt production of proteins essential to the growth and development of colorectal and other types of cancer cells. The newly identified micro-RNAs lower levels of cyclin-dependent kinases CDK4 and CDK6, blocking the growth of cancer cells. They also block some cell survival proteins, helping to initiate the natural process of cell death in tumors.
The paper appears in Cancer Research, a journal published by the American Association for Cancer Research. Amriti R. Lulla, a doctoral student in the lab of Wafik S. El-Deiry, MD, PhD, FACP, Deputy Cancer Center Director, co-Leader of the Molecular Therapeutics Program and the William Wikoff Smith Chair in Cancer Research at Fox Chase Cancer Center, performed the experiments.
Micro-RNAs are small ribonucleic acids that can turn off specific genes and can affect many cellular processes. “We discovered that expression of these micro-RNAs is lost in colorectal cancers, and that CDK4 and CDK6 were over-expressed in the same patients’ tumors, but that restoring the micro-RNAs blocked cell growth,” El-Deiry said.
Cyclin-dependent kinases (CDKs) are part of the cell cycle engine that promotes cell growth and division. A number of small molecule CDK4 and CDK6 inhibitor drugs are approved by the FDA to treat breast cancer and are being tested in clinical trials in various other tumor types. The newly discovered micro-RNA 6883 family blocks production of the CDK4 and CDK6 proteins that drive cell growth, so they have potential to be developed as a new treatment for cancer.
“We are excited to recognize this new level of control of the cell division cycle that contributes to cancer suppression,” said El-Deiry, who is credited with the discovery of the first cellular CDK inhibitor protein p21 (WAF1) in 1993. “We’ve come full circle from finding that CDKs can be blocked by cellular proteins such as p21, to small molecule CDK inhibitor drugs developed by big pharmaceutical companies to now finding the micro-RNAs that block the production of these target CDKs,” he said.
Since small molecule CDK inhibitors do not work well as single agents in colorectal cancer, Lulla and El-Deiry predict that combining these newly discovered micro-RNAs with standard chemotherapy drugs such as irinotecan already in use could become an effective new combination treatment for advanced colorectal cancer. They provide data in the paper to support these directions.
Also of note, the micro-RNAs were embedded in the PER1 gene, which influences circadian rhythms. The discovery of the genes that control circadian rhythms was awarded the Nobel Prize in Physiology and Medicine earlier this month. El-Deiry noted it is of interest and perhaps not by coincidence the same chromosomal region controls an important cell cycle arrest function through miR-6883-5p and harbors the tumor suppressive circadian rhythm gene PER1. New studies to understand this relationship are already underway.
The work was supported by an American Cancer Society Research Professorship grant to Dr. El-Deiry.