Researcher investigate 2-drug synergy to treat drug-resistant chronic myeloid leukemia
(Medical Xpress)—An interdisciplinary team of researchers has dissected a case of synergy in drug-resistant chronic myeloid leukemia to understand the mechanism by which two drugs, danusertib and bosutinib, work together to overcome resistance in the BCR-ABL gatekeeper mutation-specific disease. The team includes a researcher at Moffitt Cancer Center and colleagues at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences in Austria and the Massachusetts Institute of Technology. The goal is to address an unmet medical need because this BCR-ABL mutation confers resistance to all currently approved kinase inhibitors for chronic myeloid leukemia.
The study appeared in the Sept. 30 online version of Nature Chemical Biology.
"Treatment of chronic myeloid leukemia rapidly improved after the introduction of the first BCR-ABL inhibitor, Gleevec (imatinib)," said study co-author Uwe Rix, Ph.D., an assistant member of the Moffitt's Drug Discovery Department and Experimental Therapeutics Program. "However, it soon became apparent that a broad spectrum of possible resistance mechanisms necessitated second- and third-generation BCR-ABL inhibitors. Although these are mostly very successful, none of the currently approved options has been effective in patients with chronic myeloid leukemia who harbor the BCR-ABL gatekeeper mutation."
The researchers investigated the molecular mechanisms and logic underlying the synergistic interaction between danusertib and bosutinib, which is specific for BCR-ABL gatekeeper mutation-transformed cells. They applied a novel systems pharmacology approach involving a combination of different proteomics and gene expression profiling methods.
"We found previously unappreciated features of both agents," Rix said. "The synergy did not correlate with direct inhibition of BCR-ABL. Instead, our observations converged on the downstream MAPK signaling cascade as the predominantly affected pathway in the synergistic inhibition of BCR-ABL."
The researchers said the combination of both compounds impaired the activity of c-MYC, a gene regulator that codes a transcription factor playing a well-established but a not well understood role in a broad spectrum of human cancers.
"In the context of chronic myeloid leukemia, c-MYC is required for BCR-ABL-mediated transformation," Rix explained. "What is intriguing is that chronic myeloid leukemia cells with the BCR-ABL gatekeeper mutation seem to be more dependent on the MAPK/c-MYC signaling axis than BCR-ABL wild-type cells. Thus, challenging c-MYC with drugs appears promising in these resistant cells, but steps have only recently been made."
The researchers concluded that they have unraveled the action and impact of a "new synergistic drug interaction between danusertib and bosutinib in a clinically relevant, highly drug-resistant disease setting" by revealing a "non-obvious synergistic mechanism elicited by several off targets of the two small molecules."
"We believe this strategy of gaining a functional understanding of drug synergy may serve as a model for further mode-of-action studies," they concluded.
More information: www.nature.com/nch… bio.1085.pdf
Journal reference: Nature Chemical Biology
- Can cancer drugs combine forces? Aug 16, 2007 | not rated yet | 0
- Combination of 2 novel anti-cancer agents may help fight CML resistant to current therapy May 29, 2008 | not rated yet | 0
- Activation of LYN kinase is associated with imatinib-resistance in CML patients Jun 25, 2008 | not rated yet | 0
- Researchers discover why Gleevec-type drugs control, but do not eradicate leukemia Dec 08, 2008 | not rated yet | 0
- Targeting leukemia cell's gene 'addiction' presents new strategy for treatment Mar 03, 2010 | not rated yet | 0
- Motion perception revisited: High Phi effect challenges established motion perception assumptions Apr 23, 2013 | 3 / 5 (2) | 2
- Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update) Apr 02, 2013 | 4.5 / 5 (11) | 5
- The visual system as economist: Neural resource allocation in visual adaptation Mar 30, 2013 | 5 / 5 (2) | 9
- Separate lives: Neuronal and organismal lifespans decoupled Mar 27, 2013 | 4.9 / 5 (8) | 0
- Sizing things up: The evolutionary neurobiology of scale invariance Feb 28, 2013 | 4.8 / 5 (10) | 14
Pressure-volume curve: Elastic Recoil Pressure don't make sense
May 18, 2013 From pressure-volume curve of the lung and chest wall (attached photo), I don't understand why would the elastic recoil pressure of the lung is...
If you became brain-dead, would you want them to pull the plug?
May 17, 2013 I'd want the rest of me to stay alive. Sure it's a lousy way to live but it beats being all-the-way dead. Maybe if I make it 20 years they'll...
MRI bill question
May 15, 2013 Dear PFers, The hospital gave us a $12k bill for one MRI (head with contrast). The people I talked to at the hospital tell me that they do not...
Ratio of Hydrogen of Oxygen in Dessicated Animal Protein
May 13, 2013 As an experiment, for the past few months I've been consuming at least one portion of Jell-O or unflavored Knox gelatin per day. I'm 64, in very...
Alcohol and acetaminophen
May 13, 2013 Edit: sorry for the typo in the title , can't edit I looked around on google quite a bit and it's very hard to find precise information on the...
Marie Curie's leukemia
May 13, 2013 Does anyone know what might be the cause of Marie Curie's cancer
- More from Physics Forums - Medical Sciences
More news stories
Older prostate cancer patients with other underlying health conditions should think twice before committing to surgery or radiation therapy for their cancer, according to a multicenter study led by researchers in the UCLA ...
Cancer 8 hours ago | not rated yet | 0 |
Intensity-modulated radiation therapy has become the most commonly used type of radiation in prostate cancer, but research from the University of North Carolina suggests that the therapy may not be more effective than older, ...
Cancer 10 hours ago | not rated yet | 0
New research suggests that a compound abundant in the Mediterranean diet takes away cancer cells' "superpower" to escape death. By altering a very specific step in gene regulation, this compound essentially re-educates cancer ...
Cancer 10 hours ago | 4.8 / 5 (11) | 2 |
(HealthDay)—For young adults needing either a chest or abdominopelvic computed tomography (CT), the short-term risk of death from underlying morbidity is greater than the long-term risk of radiation-induced ...
Cancer 11 hours ago | not rated yet | 0
In a new study described in the journal Oncogene, researchers reveal how a key player in cell growth, immunity and the inflammatory response can be transformed into a primary contributor to tumor growth.
Cancer 17 hours ago | not rated yet | 0 |
Early-life exposure to traffic-related air pollution was significantly associated with higher hyperactivity scores at age 7, according to new research from the University of Cincinnati (UC) and Cincinnati Children's Hospital ...
2 hours ago | not rated yet | 0 |
(Medical Xpress)—A research team, led by Jeremy Barr, a biology post-doctoral fellow, unveils a new immune system that protects humans and animals from infection.
7 hours ago | 4.5 / 5 (11) | 2 |
Bacteria resistant to the antibiotic colistin are also commonly resistant to antimicrobial substances made by the human body, according to a study in mBio, the online open-access journal of the American Society for Microb ...
2 hours ago | 5 / 5 (1) | 0
Researchers have pinpointed a catalytic trigger for the onset of Alzheimer's disease – when the fundamental structure of a protein molecule changes to cause a chain reaction that leads to the death of neurons ...
11 hours ago | 5 / 5 (3) | 0 |
Salamanders' immune systems are key to their remarkable ability to regrow limbs, and could also underpin their ability to regenerate spinal cords, brain tissue and even parts of their hearts, scientists have ...
11 hours ago | 4.8 / 5 (6) | 2 |
Turns out, that old "practice makes perfect" adage may be overblown. New research led by Michigan State University's Zach Hambrick finds that a copious amount of practice is not enough to explain why people ...
8 hours ago | 3.3 / 5 (10) | 0 |