A new study improves the understanding of a mutation that causes resistance to targeted melanoma therapies. The mutation was determined to be present in the tumor pre-treatment and was not an acquired resistance variation that developed after treatment, as previously understood. The study findings were published in Cancer Discovery.
The original goal of the study was to understand how and why resistance develops against CDK4/MEK inhibition treatment in melanomas. One patient with stage III malignant melanoma with an NRAS mutation in the tumor responded well to initial treatment with 39% reduction in tumor burden but resistance arose quickly and the disease spread. Whole genome sequencing of the resistant tumor found a PIK3CA mutation which is known to influence tumor growth. The research team looked closely at multiple locations of the pre-treatment biopsy and determined that the mutation the PIK3CA gene was in an area on one side of the tumor not analyzed originally, emphasizing the need for multi-site sampling.
"Our study is the first to measure multiple regions in pre-treatment tumor biopsies at high resolution and then track the resistant mutation over years of treatment through six biopsies," said Lawrence Kwong, Ph.D., assistant professor of Translational Molecular Pathology. "We are able to say that this mutation started out rare and then rapidly expanded as the MEK/CDK4 inhibitors killed off a large number of non-resistant cells."
The next step was to try and identify a target that could be used to re-sensitize the tumor to the MEK/CDK4 treatment. The researchers found that inhibiting ribosomal s6 protein in mice restored the effectiveness of the drug therapy and resulted in tumor shrinkage in melanomas with a PIK3CA mutation. More research is needed to determine if s6 protein is a possible target for human drug development.