Mayo Clinic researchers clarify chemo resistance, and perhaps a new therapy

March 09, 2017

ROCHESTER, Minn. -- Mayo Clinic scientists have identified a specific protein implicated in drug resistance, as well as a possible therapeutic tool. Their work appears in the EMBO Journal.

The team led by Haojie Huang, Ph.D., a Mayo Clinic tumor biologist within Mayo Clinic's Center for Biomedical Discovery identified the role of FOXO1 in chemotherapy resistance.

They also identified a potential therapeutic tool by engineering a peptide, which is a short segment of amino acids.

Taxanes: response and resistance

Cancer medications come in many forms. One family of chemicals called taxanes is used to treat advanced cancers. However, over time taxanes can become less effective. Cancer cells reroute communication signals down other pathways. In this study, the authors looked at how this rerouting, or resistance, occurs in relation to the activity of enzymes called kinases.

Kinase ringleaders

Cells need energy to function. Kinase enzymes help by trading chemicals back and forth on specific molecules, often proteins. This activity fuels cellular functions. The authors examined the serine/threonine kinase AKT. AKT's actions generally help cells survive. But when it goes awry, this kinase plays a central role in many types of cancer. Drugs that shut down AKT have great therapeutic promise. But, because of the complexity inherent in cellular communication, those therapies themselves instead may allow cancer to survive.

New mechanism

In this new study researchers treated cancer cells with taxanes, which block, or inhibit, AKT action. They found that taxanes prevent a protein called FOXO1 from migrating out of the cell's nucleus. When FOXO1 stays put in the nucleus, another protein, ERK, becomes inappropriately active and kicks off signals that help cancer survive and develop resistance.

"This is why, despite great therapeutic promise, none of the AKT inhibitors have been approved by the Food and Drug Administration for anticancer use in clinic," explains Dr. Huang.

But, when FOXO1 does migrate out of the nucleus, it attaches to a scaffolding protein called IQGAP1. That binding action blocks the activation ERK and prevents chemotherapy resistance.

"We also found that cotreatment with a taxane and a small FOXO1-derived peptide inhibitor blocks ERK activation and tumor growth," says Dr. Huang. "Uncovering this new and important mechanism of drug resistance may, one day, allow us to develop new therapeutics to overcome the resistance to taxane and AKT inhibitory medicines in cancers which harbor genetic lesions leading to hyper-activation of AKT."

This engineered peptide inhibitor has been patented by Mayo Clinic Ventures, the commercialization arm of Mayo Clinic.
-end-
In addition to Dr. Huang, other authors are:

The authors reported no conflicts of interest. Funding for this work was provided by the National Institutes of health, the U.S. Department of Defense, Mayo Clinic Center for Individualized Medicine and the National Natural Science Foundation of China. Dr. Huang also receives funding from the Center for Biomedical Discovery.

About Mayo Clinic

Mayo Clinic is a nonprofit organization committed to clinical practice, education and research, providing expert, whole-person care to everyone who needs healing. For more information, visit mayoclinic.org/about-mayo-clinic or newsnetwork.mayoclinic.org.

Mayo Clinic

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.