Mutations In The Braf Gene Predict Sensitivity To Cancer Drugs
A team of scientists led by researchers at Memorial Sloan-Kettering Cancer Center have discovered that a new class of drugs -- now in early stage clinical trials -- work best in patients with mutations in the BRAF gene. BRAF is a protein that plays a central role in the growth and survival of cancer cells and is mutated in the majority of patients with melanoma and in a minority of patients with colon, breast, and lung cancers. The findings, available in an advance online publication of Nature, represent a potential targeted therapy tailored for patients whose tumors contain this mutation.
The scientists found that drugs that inhibit a protein called MEK selectively inhibited the growth of cancer cells lines and tumors that have a mutated BRAF gene. One of these drugs, PD0325901 (developed by Pfizer Research and Development), is now being tested in clinical trials of patients with melanoma, colon, breast, and lung cancers. In addition, by re-analyzing the data on more than 42,000 compounds tested by the National Cancer Institute against a panel of 60 cancer cell lines, the investigators were able to identify a small number of other compounds that also selectively inhibit tumors that have the BRAF mutation. While the mechanism of action of some of these compounds has yet to be determined, several of the most effective compounds were also inhibitors of the MEK protein.
"We find that all tumors with the BRAF mutation and some with the RAS mutation are sensitive to drugs that inhibit MEK," explained Dr. Neal Rosen, Professor of Medicine and a member and laboratory head in the Molecular Pharmacology and Chemistry Program at Memorial Sloan-Kettering and the study's senior author. "Translating these findings into a strategy for treating patients whose tumors are dependent upon this specific genetic change is the next step, and such clinical trials are now ongoing.".
"The BRAF mutation was first identified by a consortium of investigators searching for proteins that are frequently mutated in human cancer," said Dr. David Solit, the study's first author and a medical oncologist at Memorial Sloan-Kettering who is also a member of Dr. Rosen's laboratory. This project, an outgrowth of the Human Genome Project, called the Cancer Genome Project, has the goal of identifying the causative mutations that cause human cancers.
"This represents what we believe will be the first of a series of new drugs that specifically target cancer cells that contain mutations identified by the Cancer Genome sequencing effort," said Dr. Solit. "The hope is that these new targeted therapies will be more effective and less toxic than traditional chemotherapies.".
The study's other scientists were Christine A. Pratilas, Ayana Sawai, Andrea Basso, Qing Ye, Jose M. Lobo, and Yuhong She, all of Memorial Sloan-Kettering; Drs. Levi A.Galloway, Gad Getz, Todd R. Golub, and William R. Sellers of Dana-Farber Cancer Institute and Broad Institute of MIT and Harvard; Dr. Iman Osman of New York University Medical College; and Dr. Judith Sebolt-Leopold of Pfizer Global Research and Development.
This work was supported by grants from the National Institutes of Health, the William H. Goodwin and Alice Goodwin Foundation for Cancer Research, the Memorial Sloan-Kettering Cancer Center Experimental Therapeutics Center, the Waxman Foundation, the Howard Hughes Medical Institute, Golfers Against Cancer, and the American Society of Clinical Oncology.
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