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Researchers find drug-resistant gene for Gleevec
  • By Lee Han-soo
  • Published 2019.04.23 17:29
  • Updated 2019.04.23 17:29
  • comments 0

Researchers at St. Mary’s Hospital have discovered a new gene that causes drug resistance against Novartis’ Gleevec (Ingredient: imatinib), a blood cancer drug, the hospital said Tuesday.

From left, Professors Kim Dong-wook, Kim Hong-tae and Lee Joo-yong

Gleevec, introduced in Korea in 2001, is the first anticancer drug to increase the therapeutic effect dramatically while reducing side effects by attacking specific targets expressed only in blood cancer cells.

With the introduction of Gleevec, prospects of chronic myelogenous leukemia patients have changed from requiring bone marrow transplantation to taking the drug once a day, making possible long-term survival and even sometimes cure of the disease. However, the problem was that patients could develop resistance toward the drug after repeated use, which allowed leukemic cancer cells to proliferate infinitely and lead to death.

According to the hospital, about 10 percent of the chronic myelogenous leukemia patients are resistant to the drug, and 20 percent of the patients develop resistance after receiving treatment with Gleevec.

The team, led by Professor Kim Dong-wook of the Department of Hematology at the hospital, found that a gene called Grancalcin regulates Gleevec resistance, identifying a molecular biologic mechanism that activates TRAF6-ULK1-dependent autophagy through a leukemia animal model.

Professors Kim Hong-tae and Myung Kyung-jae of Ulsan National Institute of Science and Technology and Professor Lee Joo-yong of Chungnam National University also participated in the study.

The team identified a COBLL1 protein, which plays a crucial role in acquiring resistance to Tasigna (Ingredient: nilotinib), using a next-generation sequencing and microarray method, in March 2017.

The researchers focused on the fact that a few point mutations in the BCR-ABL1 gene, known to be the primary cause of target cancer resistance, were found in the patients. They believed another resistance mechanism was playing an essential role in developing significant resistance and confirmed it after five years of research.

“The GCA protein activates the TRAF6 protein and increases the K63-associated ubiquitination of ULK1 that stabilizes and activates the ULK1 protein, which, in turn, greatly increases the cell's self-reprogramming process,” according to the press release. “Such effect maintains the survival rate of leukemic cells despite the continued use of anticancer drugs.”

Professor Kim Dong-wook also said, “Gleevec has helped patients to treat leukemia to a great extent. However, the fact is that three out of ten patients do not respond to the drug.”

This study has identified how Gleevec resistance occurs, which will significantly increase the likelihood of developing new diagnostic methods and therapies, he added.

Autophagy published the results of the study.


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