Navigation Links
UCLA scientists uncover mechanism for melanoma drug resistance
Date:3/6/2012

Cancer is tough to kill and has many ways of evading the drugs used by oncologists to try and eliminate it.

Now, researchers at UCLA's Jonsson Comprehensive Cancer Center have uncovered how an advanced form of melanoma gets around an inhibitor, Zelboraf, which targets the mutated BRAF gene.

By examining the part of the melanoma genome that encodes proteins, called the exome, Jonsson Cancer Center scientists discovered that in some patients with BRAF-mutated metastatic melanoma, the mutated BRAF gene driving the cancer becomes amplified as the cancer develops resistance to a BRAF inhibitor. Quite simply, by increasing the copies of the mutated BRAF gene, the melanoma is trying to over produce the drug target protein and outnumber the inhibitor. The findings may lead to alternative ways of preventing or treating resistant melanomas.

"Understanding and solving the problem of how cancer gets around targeted drugs is arguably one of the highest priorities in modern day cancer medicine. In this study, we found that in some patients, the cancer simply makes more of the target, the mutated BRAF gene, so that the drug dose becomes too weak to fight the cancer," said study senior author Dr. Roger Lo, an assistant professor of dermatology and molecular and medical pharmacology and a Jonsson Cancer Center scientist. "If you think of the mutation as a right hand and the BRAF inhibitor as a left hand and the two clasp to be effective, there's clearly an optimal radio to ensure the mutated gene is fully inhibited. Here, we get more of the drug target, 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.

About 50 percent of patients with metastatic melanoma, or 4,000 people a year, have the BRAF mutation and can be treated with Zelboraf, two pills taken twice a day. Zelboraf was approved by the U.S. Food and Drug Administration for use in metastatic melanoma in August of 2011. Many other common human cancers, including colon, thyroid and lung, also harbor BRAF-mutated subsets, Lo said.

Oncologists cannot give more Zelboraf to these patients to combat the increased number of mutated BRAF genes because the dose approved by the FDA is the maximum tolerated dose, Lo said. However, Zelboraf could perhaps be given with inhibitors of other cell signaling 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 tumor tissue before treatment with Zelboraf 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, we were able to see in actual patient tissue samples how the cancer gets around this drug by altering the target," Lo said. "It appears that the drug target is not only mutated and hyper-activated, but it's also massively over-produced in some cases of clinical relapse."

Lo said 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, an oncologist might have room to increase the drug dose once a relapse driven by BRAF amplification is encountered in the clinic.

Scientists so far have discovered five mechanisms of BRAF inhibitor resistance in melanoma patients, accounting for about 60 to70 percent of patients. However, 30 to 40 percent 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. "If we know what happens in every relapse, we can have a plan in place that will help us avoid or overcome resistance," he said. About 70,000 new cases of melanoma are diagnosed each year in the United States. Of those, 8,000 people will die of the disease.


'/>"/>

Contact: Kim Irwin
kirwin@mednet.ucla.edu
310-206-2805
University of California - Los Angeles Health Sciences
Source:Eurekalert

Related medicine news :

1. No workout? No worries: Scientists prevent muscle loss in mice, despite disease and inactivity
2. New test can better predict successful IVF embryos, scientists say
3. NIH-supported scientists investigate a newly emerging staph strain
4. Scripps Florida scientists uncover inflammatory circuit that triggers breast cancer
5. UCLA scientists report link between traumatic brain injury, post-traumatic stress disorder
6. Scientists make strides toward fixing infant hearts
7. Scripps research scientists demonstrate effective new biopsy in a blood test to detect cancer
8. Scientists May Be Closer to Developing Red Wine Drug
9. Scientists Use Brain Waves to Eavesdrop on the Mind
10. Scripps research scientists illuminate cancer cells survival strategy
11. Scientists report first step in strategy for cell replacement therapy in Parkinsons disease
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:2/24/2017)... ... February 24, 2017 , ... Houston ... options at his office, Antoine Dental Center. Currently, patients can get single dental ... may apply, but patients can learn more about these offers by contacting Antoine ...
(Date:2/24/2017)... ... ... The Smart Machine Age is here, and it’s disrupting everything. Not only could it ... the United States may be taken over by technology in the next five to ... over colleagues is drawing to a close. Success will belong to those who can ...
(Date:2/24/2017)... ... February 24, 2017 , ... With ProGlass Prism users now have the ability ... total control over position, rotation, distortion, edge softness, edge blur, chromatic aberration, individual glass ... , With ProGlass Prism users are given the tools and effects to generate ...
(Date:2/24/2017)... ... February 24, 2017 , ... The Radiology Business Management ... radiology marketing programs at the annual Building Better Radiology Marketing Programs conference, ... Hotel in Fort Worth, Texas. Nine awards are given out in five categories. They ...
(Date:2/23/2017)... ... February 23, 2017 , ... On February 22, 2017 the ... to withdraw previous guidance issued by the Obama Administration requiring schools to ... May 2016 by the Obama Administration came in response to a growing number ...
Breaking Medicine News(10 mins):
(Date:2/24/2017)... , Feb. 24, 2017  Xynomic Pharmaceuticals, Inc., an ... that it has acquired exclusive worldwide rights to ... innovative HDAC inhibitor targeting hematological and solid tumors. ... Phase 1 and 2 clinical trials of Abexinostat ... have already been completed, demonstrating that Abexinostat ...
(Date:2/23/2017)... 23, 2017 Visiomed, the French leader ... 1997, is changing the landscape of healthcare with ... with pro-active, custom-made solutions. Recognizing the rising demand ... affordable healthcare without walls, Visiomed has launched BewellConnect, ... with healthcare professionals that is empowering the lives ...
(Date:2/23/2017)... 2017  Genesis Healthcare Services has merged with Hospice ... by Bill Monast , President and CEO of ... Nathan Feltman , executives with Home Health Depot, Inc., ... This acquisition helps Hospice Cloud maintain its ... durable medical equipment (DME) solutions for the hospice industry. ...
Breaking Medicine Technology: