Nearly half of all patients with malignant melanoma, the most deadly form of skin cancer, have a mutation in the BRAF gene found in their tumors. Mutations in the BRAF gene turn on a cancer growth switch known as the MAP kinase pathway.
In recent years, new drugs have been approved that target the BRAF/MAPK pathway, but after a few months or years of treatment the cancer becomes resistant to anti-BRAF therapy and the tumors start to grow again.
Vanderbilt-Ingram Cancer Center (VICC) investigators Jeffrey Sosman, M.D., Douglas Johnson, M.D., MSCI, and Kimberly Dahlman, Ph.D., in collaboration with researchers at the University of California at Los Angeles (UCLA) Jonsson Comprehensive Cancer Center, have discovered some of the changes that are occurring inside cancer cells which lead to this treatment resistance.
The three-year study, led by Roger Lo, M.D., Ph.D., associate professor of Dermatology at UCLA, was posted online last month in advance of publication in the journal Cell.
The investigators analyzed samples from melanoma patient tumors both before therapy and after the disease recurred. They also modeled drug resistance in the lab by growing melanoma cell lines from patients’ tumors and adapting them to drugs that block the MAP kinase pathway.
“Early in the process we realized we could not explain how the tumors change during treatment just by analyzing for gene mutations,” said Johnson.
Instead, they used two techniques: one to detect all of the changes in genes’ activities inside the tumors, and the second to investigate the function of immune cells in and around the tumors.
They found that a gene activity regulatory mechanism (called CpG methylation) triggered a wide range of altered behaviors inside the tumor cells.
They also found distinct patterns in the way genes are switched on or off in melanoma and that these patterns may be even more common than gene mutations.
The investigators discovered new clues that explain why tumors also develop resistance to new immunotherapy drugs.
“We found resistance to gene therapies can develop at the same time that anti-tumor immune cells are becoming weaker. So in some patients the melanoma may slowly develop resistance to both the anti-BRAF therapies as well as immunotherapies,” said Sosman, who is director of the Melanoma and Tumor Immunotherapy Program at VICC.
Dahlman said the investigators are hopeful that the findings can lead to earlier detection of drug resistance in patients, as well as new ways to suppress or target the resistance.
Funding for the study was provided by the National Cancer Institute (CA168585, CA 176111), Melanoma Research Alliance, SWOG/Hope Foundation, Cancer Research Institute and Stand Up to Cancer (SU2C).