Groundbreaking research into a promising new class of drugs called BRAF inhibitors led by UCLA Jonsson Comprehensive Cancer Center member Dr. Roger Lo has been selected by the American Association for Cancer Research (AACR) for inclusion in “The Best of AACR Journals 2014,” the organization’s annual review highlighting its journals’ most highly cited and influential studies of the year.
Lo’s work, which provides critical insight into the key mutations and cell-signaling pathways BRAF-mutant melanoma cells use to become resistant to inhibitor drugs, is featured as one of the year’s major achievements in cancer research.
The AACR will be highlighting his study at its upcoming Annual Meeting on April 17, 2016.
Approximately 50 percent of advanced melanoma tumors—the deadliest form of skin cancer, which can spread throughout the body—are driven to grow by the presence of BRAF mutations. BRAF inhibitors have shown unprecedented responses as a treatment for these types of tumors, rapidly shrinking them. However, BRAF-mutated tumors frequently show early resistance to treatment and respond only partially to BRAF inhibitors, leaving behind cancer cells that lead to eventual tumor regrowth.
In his study, Lo, an associate professor of dermatology and molecular and medical pharmacology at UCLA, discovered how tumor cells escaped the effects of BRAF inhibitors based on the outgrowth of melanoma cells that had been selected by therapy to rely on different mutations and cell-signaling pathways to thrive in the presence of BRAF-inhibitor therapy. This work was based on the analysis of 100 biopsies from patients treated with BRAF inhibitors, and it highlights that advanced BRAF-mutated melanoma tumors harbor extensive reservoir of genetic diversity to escape from the potency of BRAF inhibitors within a matter of months.
The study shows how, within individual patients, multiple clones and mechanisms of resistance can arise during the course of therapy. These fundamental insights provide cancer researchers and physicians a realistic assessment of the challenges posed by therapy resistance in the clinic rather than in simpler experimental models often used in the laboratories.
The findings also suggested common-denominator strategies to potentially forestall resistance, including one, led by Dr. Antoni Ribas, professor of hematology and oncology at UCLA, that is already in clinical testing combining three targeted therapy agents
Lo’s work provides researchers with powerful information that can be translated directly into the clinic, specifically to improve the use of BRAF inhibitor drugs in combination with other potential drugs for melanoma patients. As doctors learn what these mechanisms of tumor resistance are, they can combine inhibitor drugs that block multiple resistance routes and eventually make the tumors shrink for much longer, or go away completely.
The AACR’s recognition of Lo’s study highlights the work of UCLA’s translational physician-scientists who are taking laboratory discoveries to cancer patients as quickly as possible.
Lo’s study, entitled “Acquired Resistance and Clonal Evolution in Melanoma during BRAF Inhibitor Therapy,” was published online November 21, 2013 in the journal Cancer Discovery.
This work represents an international collaboration led by Dr. Lo, which includes scientists from Vanderbilt University in Nashville, Tennessee, the Melanoma Institute of Australia in Sydney, Australia, and the Ludwig Institute for Cancer Research in Brussels, Belgium.
