Institute research discovers epitranscriptomic causes of drug resistance
A major breakthrough in understanding the cause of drug resistance in leukemia was published in Cell Research this week based on the discoveries by Dr. Shujun Liu, head of the Cancer Epigenetics and Experimental Therapeutics section at The Hormel Institute. Dr. Liu and his team studied the molecular causes for the development and maintenance of drug resistant phenotypes in leukemia, and looked for new therapeutic options based on that process to cure this blood cancer.
Dr. Liu’s study specifically focuses on the epigenetic role of a mRNA demethylase called Fat Mass and Obesity-Associated Protein (FTO) and a mRNA modification called N6-methyladenosine (m6A) in regulating leukemia cell fate decision, whether a cell will die or survive and become resistance, in response to molecular-targeting therapies. The article, “A Dynamic N6-Methyladenosine Methylome Regulates Intrinsic and Acquired Resistance to Tyrosine Kinase Inhibitors” was a collaboration with other researchers from Mayo Clinic and University of Chicago, including Drs. Fei Yan, Aref Al-Kali, Zijie Zhang, Jun Liu, Jiuxia Pang, Na Zhao, Chuan He, and Mark R. Litzow.
Tyrosine kinase inhibitors (TKIs) are a type of targeted therapy used to treat leukemia and other cancers. Many patients initially respond well to TKI therapies but the disease almost always progresses and TKI resistant phenotypes rapidly appear. The appearance of TKI resistant phenotypes cause leukemia cells to escape cell death from TKI therapies. . Because of the resistance, leukemia remains a dangerous disease for many patients.
“We present evidence showing that the development of resistant phenotypes during TKI therapy depends on leukemia cells making too much FTO, which causes the m6A level to go down,” said Dr. Liu. “When the m6A methylation is restored, the drug resistant cells re-gain sensitivity to TKI therapies.”
“This discovery is critically important because resistance to treatment is what prevents patients from being cured,” said Dr. Liu.
“We are excited because it furthers our mission to find discoveries that help control cancer which will allow people to live longer, healthier lives.”
The discoveries of Dr. Liu and his team suggest that special drug inhibitors could be therapeutically used before and after a main leukemia treatment. This would prevent or overcome drug resistance thereby allowing the treatment to be more effective. Through discoveries in cancer research, the overall five-year relative survival rate for leukemia has more than quadrupled since 1960. Leukemia remains a dangerous cancer and The Hormel Institute cancer researchers are dedicated to furthering discoveries.