By Wendy Bindeman
While 60 percent of people with metastatic melanoma, an aggressive type of skin cancer, have multiple treatment options available to them, roughly 40 percent either do not respond to treatment, or relapse.
A recent paper by the research group of Ann Richmond, professor of pharmacology, published in Clinical Cancer Research, describes a new therapeutic target and potential treatments for metastatic melanoma.
Melanoma tumors often have mutations in MDM2, a protein that normally inhibits the tumor suppressing p53 protein. These mutations make MDM2 overactive, thereby causing rapid breakdown of p53. Since the main responsibility of p53 is to stop a cell from dividing, excessive inhibition by MDM2 can drive tumor growth.
The Richmond group evaluated the investigational agent KRT-232, an inhibitor of MDM2, for use in metastatic melanoma. They treated mice that had been implanted with cells from human melanoma tumors with either KRT-232 alone, or with KRT-232 in combination with two protein inhibitors that are considered to be the standard of care for melanoma: dabrafenib, a BRAF inhibitor, and trametinib, an MEK inhibitor. BRAF and MEK are both growth-promoting proteins: BRAF is often mutated in melanoma, and MEK helps transmit signals from BRAF, so inhibiting the two together is necessary in order to stop out-of-control growth.
The scientists identified three classes of tumors: (1) those that responded best to dabrafenib and trametinib (D + T) but did not benefit from KRT-232; (2) those that responded well to D + T + KRT-232 but not to treatment with just D + T or just KRT-232; and (3) those that responded to KRT-232 alone, but did not benefit from the other inhibitors. Which group a tumor belonged to depended on whether it had mutations in BRAF and some other closely related growth-promoting proteins.
The authors were also interested in combining KRT-232 with navitoclax, a BCL-2 inhibitor (BCL-2 is a protein that prevents cell death), because previous studies in acute myeloid leukemia suggested that combining BCL-2 and MDM2 inhibition could effectively kill cancer cells that are resistant to MDM2 inhibitors by themselves. In this study, combining navitoclax and KRT-232 worked in tumors that had mutant BRAF, but not those that had normal BRAF.
KRT-232, alone or as part of a combination, is a promising therapy for metastatic melanoma that does not respond to the standard therapy with dabrafenib and trametinib. Additionally, mutations in BRAF appear to be biomarkers that can help identify which tumors will respond to which therapeutic strategy. This gene is routinely tested when a patient gets evaluated for treatment, so clinicians can use that information to choose the drug combination that is most likely to work for each patient.
This research was supported by the National Institutes of Health, the National Cancer Institute, the U.S. Department of Veterans Affairs, Harry J Lloyd Charitable Trust, and Breast Cancer Research Foundation.