Navigation Links
Moffitt researcher investigates 2-drug synergy to treat drug-resistant chronic myeloid leukemia

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.

Contact: Kim Polacek
H. Lee Moffitt Cancer Center & Research Institute

Related medicine news :

1. Moffitt researchers find cancer therapies affect cognitive functioning among breast cancer survivors
2. Moffitt Cancer Center researchers: Quality of life as important as quantity of life
3. Moffitt Cancer Center researchers working at frontiers of melanoma research
4. Moffitt researchers find adolescents with cancer concerned about their future reproductive health
5. Moffitt researcher publishes book on nutritional management of cancer treatment effects
6. Moffitt researcher awarded GE grant to develop tool to detect breast cancer metastasis genetic risks
7. Researchers creating designer lymph nodes based on Moffitts Total Cancer Care initiative
8. Moffitt Cancer Center researchers identify drivers of sarcoma growth and survival
9. Moffitt Cancer Center researchers develop and test new anti-cancer vaccine
10. Moffitt researcher, colleagues find success with new immune approach to fighting some cancers
11. Moffitt researchers: Darwins principles say cancer will always evolve to resist treatment
Post Your Comments:
(Date:11/26/2015)... ... November 26, 2015 , ... WorldCare ... participated in the 61st annual Employee Benefits Conference. The Employee Benefits Conference was ... November 8th through Wednesday, November 11th, 2015. The conference was held at the ...
(Date:11/26/2015)... ... November 26, 2015 , ... ... has collaborated with Women’s Web – an online resource for Indian women ... mental and emotional well-being relationship, life balance, stress, professional development, and lifestyle. ...
(Date:11/25/2015)... , ... November 25, 2015 , ... ... more aggressive than those found on mammography, according to a study published online ... additional cancers not seen on mammography may necessitate a change in treatment. , ...
(Date:11/25/2015)... ... November 25, 2015 , ... The holiday season ... and pleasing the palates of attendees is of the utmost importance. Whether you ... seasonal get-together, give these recipes a try this holiday season. , Turkey Croquettes ...
(Date:11/25/2015)... ... November 25, 2015 , ... Medical Solutions, one ... for its stellar workplace culture with the company’s Cincinnati office being named a ... Cincinnati office was named a finalist in Cincinnati Business Courier’s 13th annual Greater ...
Breaking Medicine News(10 mins):
(Date:11/26/2015)... 2015 --> ... combineert immunotherapie met Bremachlorin-photodynamische therapie voor de ... ) --> ... ) Uit een ... (LUMC) blijkt dat ...
(Date:11/26/2015)... , November 26, 2015 ... addition of the "2016 Future Horizons ... of Abuse Testing Market: Supplier Shares, Country ... report to their offering. --> ... the "2016 Future Horizons and Growth ...
(Date:11/26/2015)... November 26, 2015 ... addition of the  "2016 Future Horizons ... Therapeutic Drug Monitoring (TDM) Market: Supplier ... Emerging Opportunities"  report to their offering.  ... announced the addition of the  "2016 ...
Breaking Medicine Technology: