Moffitt Researchers Discover Mechanism Leading to Drug Resistance, Metastasis in Melanoma Patients

The gist: New research suggests that some melanoma patients might benefit from a treatment schedule that alternates BRAF inhibitor drugs with MEK inhibitor drugs. The scientists hypothesize that this schedule could help prevent drug resistance and metastasis. The researchers set out to figure out why patients who receive BRAF inhibitors develop more metastases than patients on standard chemotherapy. They found that unusually high activity of a protein called EphA2 on cancer cells may be the culprit. Taking away BRAF inhibitors seemed to lower the aggressiveness of these cells. So, periodically taking away BRAF inhibitors from patients might theoretically help stave off resistance and metastasis.

Moffitt Cancer Center researchers have discovered a mechanism that leads to resistance to targeted therapy in melanoma patients and are investigating strategies to counteract it. Targeted biological therapy can reduce toxicity and improve outcomes for many cancer patients, when compared to the adverse effects of standard chemotherapeutic drugs.  However, patients often develop resistance to these targeted therapies, resulting in more aggressive cells that can spread to other sites or cause regrowth of primary tumors.

“B-Raf is a protein that is frequently mutated in human cancers, leading to increased tumor cell growth, survival and migration.  Drugs that target B-Raf or another protein in the same network called MEK have proved effective in clinical trials. Several B-Raf and MEK inhibitors have been approved with the combination of a B-Raf and a MEK inhibitor being the current standard of care for patients with B-Raf mutant melanoma. However over time many patients become resistant to B-Raf and B-Raf/MEK inhibitor therapy.

“Moffitt researchers found that patients who are on B-Raf inhibitor drugs develop more new metastases than patients who are on standard chemotherapy. The researchers wanted to determine how this acquired resistance develops in order to devise better treatment options for patients. They found that melanoma cells that are resistant to B-Raf inhibitors tend to be more aggressive and invasive, thereby allowing the tumor to spread to a new organ site.  They used a large screening approach and discovered that this resistance and aggressive behavior was due to high activity of a cell surface protein called EphA2, which is also found on glioblastoma stem cells.”