UCLA. US: Researchers at the UCLA Jonsson Comprehensive Cancer Center
have uncovered how melanoma becomes resistant to a new drug combination
therapy consisting of BRAF+MEK inhibitor — chemical compounds used to
fight cancer.
During the two-year study led by Dr. Roger Lo, the research team took
43 tumor samples from 15 patients before they were prescribed the new
BRAF+MEK inhibitors and then after the patients relapsed after the
melanoma developed resistance to the drug therapy. The participants had
all benefited from the combo therapy initially, but after a timeframe of
a few months to more than a year, the tumors that had initially
regressed, started to grow again.
After obtaining biopsies of the tumors, the researchers extracted and
analyzed the genetic material. This analysis provided leads for the
investigators to study how melanoma cells grown in Lo’s laboratory
rewired their growth circuitry to get around the combo inhibitors.
Lo’s team found that the melanoma cells resist the combo therapy of
BRAF+MEK inhibitors by developing highly unusual changes in certain key
cancer genes. These signature changes or configurations not only mark
the presence of drug resistance melanoma cells but also indicate to
researchers potential new ways to shut them off.
“We need to find ways to go beyond the BRAF+MEK drug combination, by
possibly finding a third drug, or alter how we prescribe the combo of
drugs,” said Lo, UCLA assistant professor of dermatology. “The idea is
to eventual suppress melanoma drug resistance even before it arises.”
“In most cases, melanoma eventually becomes resistant,” said Dr.
Antoni Ribas, JCCC member and professor of hematology and oncology, and a
co-author of the study. “We now understand the molecular basis of the
resistance mechanisms, which leads to the planning of new treatment
approaches to disable these mechanisms.”
An estimated 70,000 new cases of melanoma are diagnosed each year in
the United States. Of those with advanced stage or metastatic melanoma,
about 8,000 people will die of the disease each year. About 50 percent
of people with metastatic melanoma, have tumors that harbor a mutated
protein called a mutated BRAF protein. The presence of this mutated BRAF
protein is what makes a patient with metastatic melanoma appropriate
for the BRAF+MEK combo inhibitor therapy.
Lo and Ribas previously collaborated on several seminal drug
resistance studies investigating how melanoma resisted the
then-experimental drug PLX4032, which is now known as Zelboraf
(vemurafenib) and was approved by the FDA in 2011.
These studies have provided critical insights that led to development
of the current combo therapy for melanoma using BRAF+MEK inhibitors and
additional on-going clinical trials. Lo hopes this new study will also
lead to more effective therapies for patients.
“If we understand how a disease fights your therapy, then we can start to design more effective treatment strategies,” Lo said.
The study is published online today in the journal Cancer Cell.
The research was funded by the National Institutes of Health (NIH), the Melanoma Research Alliance, and Stand Up To Cancer.