Scientists uncover a new mechanism for vemurafenib resistance - currently five mechanisms of resistance known to this BRAF inhibitor
One third of melanoma patients are relapsing to a BRAF inhibitor by as yet uncovered mechanisms
- Date : 13 Mar 2012
- Topic : Melanoma
By examining the part of the melanoma exome, scientists discovered that in some patients with BRAF-mutated metastatic melanoma the mutated BRAF gene becomes amplified as the tumour develops a resistance to a BRAF inhibitor - vemurafenib. The finding may lead to alternative ways of preventing or treating resistant melanomas.
Understanding and solving the problem of how cancer develops resistance to targeted drugs is one of the highest priorities in modern day cancer medicine. In this study, scientists found that in some patients, the cancer simply makes more of the target, the mutated BRAF gene, which has the same effect as dropping the drug level.
The one-year study is published March 6, 2012, in the peer-reviewed journal Nature Communications. Study senior author is Dr. Roger Lo, an assistant professor of dermatology and molecular and medical pharmacology and a UCLA's Jonsson Cancer Centre scientist.
Developing a resistance to targeted agents
About 50% of patients with metastatic melanoma have the BRAF mutation and can be treated with vemurafenib. Many other common human cancers, including colon, thyroid and lung, also harbour BRAF-mutated subsets.
Oncologists can not give more drug to these patients to combat the increased number of mutated BRAF genes because the dose approved by medical agencies is the maximum tolerated dose. However, vemurafenib could perhaps be given with inhibitors of other cell signalling pathways in metastatic melanoma to try and stop patients from becoming resistant.
Lo and his team examined samples of 20 patients for this study, taking their normal tissue, their tumour tissue before treatment with vemurafenib and a sample when the cancer had responded earlier but subsequently became resistant. Using high-throughput DNA sequencing technology, the scientists examined the entire cancer exome to see what changes were occurring that may point to resistant mechanisms. Lo found that five of the 20 patients showed increased copies of the mutated BRAF gene. Cell lines developed from melanoma patients also showed pathways downstream of the amplified gene that could be blocked with inhibitors to fight resistance.
For the first time, scientists were able to see in actual patient tissue samples how the cancer gets around this drug by altering the target.
There's an experimental drug that also inhibits mutated BRAF which may be effective against this form of melanoma at a dose that does not result in substantial side effects. In that case, oncologists might have room to increase the drug dose once a relapse driven by BRAF amplification is encountered in the clinic.
Currently five mechanisms known of BRAF inhibitor resistance
Scientists so far have discovered five mechanisms of BRAF inhibitor resistance in melanoma patients, accounting for about 60 to70% of patients. However, 30 to 40% of patients are relapsing by as yet uncovered mechanisms.
Going forward, Lo and his team will seek to find out what is happening molecularly in every patient that relapses after therapy, so novel combination drug strategies can be developed to help them.
The one-year study was funded by the Bud and Sue Selig Innovative Research Grant from Stand Up to Cancer, Burroughs Wellcome Fund, the Seaver Institute and the Richard C. Seaver Charitable Trust. Additional support came from the USA National Cancer Institute, the V Foundation for Cancer Research, Melanoma Research Foundation, Melanoma Research Alliance, American Skin Association, Caltech-UCLA Joint Centre for Translational Medicine, Sidney Kimmel Foundation for Cancer Research, Wendy and Ken Ruby and Louis Belley and Richard Schnarr.
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