Navigation Links
BRAF inhibitor treatment causes melanoma cells to shift how they produce energy
Date:3/8/2013

A multi-institutional study has revealed that BRAF-positive metastatic malignant melanomas develop resistance to treatment with drugs targeting the BRAF/MEK growth pathway through a major change in metabolism. The findings, which will be published in Cancer Cell and have been released online, suggest a strategy to improve the effectiveness of currently available targeted therapies.

"We were surprised to find that melanoma cells treated with the BRAF inhibitor vemurafenib dramatically change the way they produce energy to stay alive," says David E. Fisher, MD, PhD, chief of Dermatology at Massachusetts General Hospital (MGH) and a co-corresponding author of the Cancer Cell paper. "While current BRAF inhibitor treatment is a major improvement shrinking tumors in most patients and extending survival for several months patients eventually relapse. So there is an ongoing need to improve both the magnitude and durability of these responses."

In about half the cases of malignant melanoma the most deadly form of skin cancer tumor growth is driven by mutations in the BRAF gene. Research by investigators at the MGH Cancer Center and elsewhere has shown that treatment with drugs that block BRAF activity temporarily halts tumor growth. Combining a BRAF inhibitor with a drug that targets MEK, another protein in the same growth pathway, strengthens and extends the antitumor response. The current study was designed to investigate how BRAF inhibition changes metabolic activity within melanoma cells and to find other possible treatment targets.

The most common way that cells convert glucose into energy is called oxidative phosphorylation and largely relies on the activity of the cellular structures called mitochondria. Many cancer cells use an alternative mechanism that produces the energy compound ATP without involving mitochondria. A series of experiments by the MGH team revealed that the elevated BRAF activity in BRAF-positive melanoma cells suppresses oxidative phosphorylation by reducing expression of a transcription factor called MITF. Suppressing production of MITF reduced levels of a protein called PGC1α that regulates the generation and function of mitochondria. But melanoma cells treated with a BRAF inhibitor showed elevated MITF activity, along with increased expression of oxidative phosphorylation genes and greater numbers of mitochondria. By switching to oxidative phosphorylation to supply the energy they need, the tumor cells increased their ability to survive in spite of BRAF inhibitor treatment.

"These findings suggest that combination treatment with mitochondrial inhibitors could improve the efficacy of BRAF inhibitors in malignant melanoma," says Fisher, the Wigglesworth Professor of Dermatology at Harvard Medical School. "Several small molecules that target mitochondrial metabolism have been identified by investigators here at the MGH and elsewhere, and laboratory investigations of specific combinations of BRAF inhibitors with mitochondrial antagonists are currently underway."


'/>"/>

Contact: Michelle Marcella
mmarcella@partners.org
617-724-2755
Massachusetts General Hospital
Source:Eurekalert

Related medicine news :

1. Breast cancer clinical trial tests combo of heat shock protein inhibitor and hormonal therapy
2. VyGone Inhibitor Zapper: The Brand New Solution For the Safe Treatment Of Sores, Warts and Herpes
3. Inhibitors of shuttle molecule show promise in acute leukemia
4. Leukemia inhibitory factor may be a promising target against pancreatic cancer
5. Uncommon BRAF mutation in melanoma sensitive to MEK inhibitor drug therapy
6. Preclinical data support ongoing clinical trials testing IDO inhibitors as a treatment for cancer
7. PARP inhibitors may have clinical utility in HER2-positive breast cancers
8. New mechanism of action for PARP inhibitors discovered
9. PI3-kinase and PARP inhibitor combo may offer new treatment option for triple-neg breast cancers
10. Scientists at Mainz University identify inhibitor of myelin formation in the central nervous system
11. New small molecule inhibitor could be a safe and first-line treatment for metastatic breast cancer
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:2/26/2017)... ... February 26, 2017 , ... ... technology standard in staffing, scheduling, and reporting for healthcare organizations. This comprehensive ... throughout the entire staffing process. StaffBridge technology improves staffing efficiency, maximizes resource ...
(Date:2/24/2017)... MN (PRWEB) , ... February 24, 2017 , ... ... of its newly designed TaskMate Go. Core benefits and advantages built into the ... and a stylish, functional look and feel. Ability to gain the benefits embedded ...
(Date:2/24/2017)... ... February 24, 2017 , ... Dr. Ronald ... officially announced the appointment of Peter A. Bell, DO, MBA, HPF, FACOEP-dist., FACEP, ... (LUCOM), beginning April 10. Dr. Bell comes to Liberty from the Ohio University ...
(Date:2/24/2017)... ... February 24, 2017 , ... The narrative in “ Signal 8: ... ’s true account of his paramedic experiences. Schanssema describes the tragedies he saw, as ... attempts to overcome them. , Schanssema, initially unsure of the career path he wanted ...
(Date:2/24/2017)... ... February 24, 2017 , ... Indiana Fiber Network (IFN) President ... later this year. Dyer started as the Chairman of the Management Committee when ... of the corporation including the recruitment of investor/owners and development of the business plan. ...
Breaking Medicine News(10 mins):
(Date:2/24/2017)... ITL Limited, ( ASX : ITD ), une société de ... excellents résultats semestriels clos le 31 décembre 2016 par ... « Résultats et mise à jour sur la croissance biomédicale ... Faits marquants Bénéfice ... hausse de 104 %) Bénéfice par action ...
(Date:2/24/2017)... 23, 2017 Non-alcoholic steatohepataitis (NASH) ... various drugs being developed for the treatment ... drugs that are in various phases of ... focuses on novel pharmacologic drugs & regenerative ... therapies, recombinant proteins and RNA-based therapeutics, but ...
(Date:2/24/2017)... Feb. 24, 2017  Xynomic Pharmaceuticals, Inc., an oncology ... it has acquired exclusive worldwide rights to develop, ... HDAC inhibitor targeting hematological and solid tumors. ... 1 and 2 clinical trials of Abexinostat in ... have already been completed, demonstrating that Abexinostat is ...
Breaking Medicine Technology: