Navigation Links
UCLA researchers discover drug resistance mechanisms in most common form of melanoma
Date:11/24/2010

Researchers with UCLA's Jonsson Comprehensive Cancer Center have found that melanoma patients whose cancers are caused by mutation of the BRAF gene become resistant to a promising targeted treatment through another genetic mutation or the overexpression of a cell surface protein, both driving survival of the cancer and accounting for relapse.

The study, published Nov. 24, 2010, in the early online edition of the peer-reviewed journal Nature, could result in the development of new targeted therapies to fight resistance once the patient stops responding and the cancer begins to grow again, said Dr. Roger Lo, senior author of the study.

In a clinical trial at UCLA's Jonsson Cancer Center and other locations, patients with BRAF-mutated metastatic melanoma have been responding very well to an experimental drug, PLX4032. However, the responses are short lived, averaging seven to nine months in duration, because the cancer gets around the blockade put up by PLX4032, which targets the BRAF mutation found in 50 to 60 percent of melanoma patients.

Lo and his team spent two years studying tissue taken from patients enrolled in the Jonsson Cancer Center study to try to determine the mechanism of resistance. They also developed drug resistant cell lines to study, in collaboration with another team at UCLA's Jonsson Cancer Center led by Dr. Antoni Ribas, an associate professor of hematology/oncology

It had been theorized that BRAF was finding a way around the experimental drug by developing a secondary mutation. However, Lo determined that was not the case, an important finding because it means that second generation drugs targeting BRAF would not work and therefore should not be developed, saving precious time.

Lo said that while his team was studying resistance, they expected to find secondary mutations in BRAF.

"We were surprised that we couldn't find a single case where a secondary mutation in BRAF was driving drug resistance," said Lo, an assistant professor of dermatology. "In a big portion of cases where cancers acquire resistance to targeted drugs, the oncogene being targeted finds a way to get around the drug by developing other additional mutations."

Cancers, Lo said, are very adept at finding ways around the drugs being used to fight them.

"You hit it with an axe, but the cancer soon finds a way to mitigate the effects of the axe," he said.

Lo and his team found that these mutually exclusive mechanisms of acquired drug resistance account for about 40 percent of the patients who were treated with PLX4032 and later acquired resistance to it. In some cases, Lo found that the cancer cells began overexpressing a cell surface protein that created an alternate survival pathway for the cancer while the BRAF survival pathway was being blocked by PLX4032. In other cases, a second oncogene, NRAS, became mutated, allowing the cancer to short circuit the PLX4032-inhibited BRAF mutation and reactivate the BRAF survival pathway. PLX4032 does not target the NRAS mutation, so the cancer can begin to regrow.

Lo said he expects to find other mechanisms of resistance in the remaining 60 percent of relapsing patients where neither of the two new mechanisms were found.

"It's important to find all the mechanisms of acquired drug resistance in this type of melanoma and figure out how to target them using drugs designed to hit those specific mechanisms," he said. "We've found two mechanisms in two subsets of melanoma and we'll need different drugs to treat those two subsets."

Going forward, Lo and his team will study the resistance mechanisms of the two subsets discovered and any others uncovered later to perhaps find better targets for therapy. For example, targeting the cell surface protein overexpression may prove more difficult than finding what causes the overexpression further upstream and homing in on that.

"How does the cell surface receptor get turned on in the first place?" Lo said. "We need to trace it back to its origin, find out what machinery is turning it on and shut that down."

Lo's study is an example of the translational research focus at the Jonsson Cancer Center. The tissues from the patients in the clinic were studied in the lab, where Lo and his team found what was causing resistance in some cases. That information will be used to find drugs to target those mechanisms that will then be brought back into the clinic to be tested in clinical trials.

"Working with the patients and then working in the lab gives me a different perspective," Lo said. "When patients ask what will happen to them if the experimental drug stops working, we can tell them that we're working 24/7 in our laboratory to figure out why that happens and discover a way to stop it."


'/>"/>

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

Related medicine news :

1. Researchers shine light on how some melanoma tumors evade drug treatment
2. New function of gene in promoting cancer found by VCU researchers
3. Stanford researchers first to turn normal cells into 3-D cancers in tissue culture dishes
4. Researchers find new target for stopping tumors developing their own blood supply
5. Researchers identify PTSD measures for use in traumatic brain injury research
6. New insight into the cause of common dementia found by researchers at Mayo Clinic
7. Researchers fight Americas other drug problem
8. Researchers map the way to personalised treatment for ovarian cancer
9. Four NYU researchers receive New York Academy of Sciences 2010 Young Scientists awards
10. AAPS presents awards to exemplary researchers
11. Yerkes researchers present at 40th Annual Society for Neuroscience Conference
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:6/25/2016)... ... 25, 2016 , ... As a lifelong Southern Californian, Dr. Omkar Marathe earned ... the David Geffen School of Medicine at UCLA. He trained in Internal Medicine at ... fellowship in hematology/oncology at the UCLA-Olive View-Cedars Sinai program where he had the opportunity ...
(Date:6/25/2016)... ... June 25, 2016 , ... Conventional wisdom preaches the benefits of moderation, whether ... latter, setting the bar too high can result in disappointment, perhaps even self-loathing. However, ... their goal. , Research from PsychTests.com reveals that behind the tendency ...
(Date:6/24/2016)... ... June 24, 2016 , ... June 19, 2016 is ... associated with chronic pain and the benefits of holistic treatments, Serenity Recovery Center ... suffering with Sickle Cell Disease. , Sickle Cell Disease (SCD) is a disorder of ...
(Date:6/24/2016)... ... 2016 , ... Global law firm Greenberg Traurig, P.A. announced that 20 Florida ... their peers for this recognition are considered among the top 2 percent of lawyers ... as members of this year’s Legal Elite Hall of Fame: Miami Shareholders Mark ...
(Date:6/24/2016)... ... ... Inc, makers of Topricin and MyPainAway Pain Relief Products, join The ‘Business for a Fair ... hour by 2020 and then adjusting it yearly to increase at the same rate as ... the wage floor does not erode again, and make future increases more predictable. , The ...
Breaking Medicine News(10 mins):
(Date:6/23/2016)... , June 23, 2016 Research ... MEMS Devices Medical Market Analysis 2016 - Forecast to 2022" ... The report contains up to date financial data ... analysis. Assessment of major trends with potential impact on the ... analysis of market segmentation which comprises of sub markets, regional ...
(Date:6/23/2016)... 23, 2016 Bracket , a leading clinical ... generation clinical outcomes platform, Bracket eCOA (SM) 6.0, at ... 26 – 30, 2016 in Philadelphia , ... Outcome Assessment product of its kind to fully integrate with ... Bracket eCOA 6.0 is a flexible platform for electronic clinical ...
(Date:6/23/2016)... -- Astellas today announced the establishment of Astellas Farma Colombia (AFC), a new affiliate with operations headquartered in ... . ... ... ... Astellas is ...
Breaking Medicine Technology: