Effects of Pak Kinase Inhibition on Emergence of Vemurafenib Resistance in Melanoma

Melanoma is considered the most dangerous form of skin cancer, and the number of cases of melanoma per year has doubled in 30 years. Mutations in the B-RAF gene account for approximately 50% of genetic driver mutations in skin melanoma. Patients with B-RAF mutant melanoma are typically treated with a chemotherapy drug called vemurafenib. However, patients can stop responding to this treatment in as little as six months. The main purpose of this study was to determine if inhibiting PAK, a kinase-signaling molecule, in combination with vemurafenib could prevent the treatment-resistance in melanoma. PAK signaling plays an important role in the Hippo tumor suppressor pathway, which is important in cell proliferation and growth. In order to evaluate the effects of PAK kinase inhibition, we utilized a drug called FRAX-486, which is a type of PAK kinase inhibitor in combination with vemurafenib to treat melanoma cells in cell growth experiments. The main findings suggest that PAK inhibition with vemurafenib prevents cell proliferation in the cancer cells. Therefore, these results support the conclusion that PAK kinase inhibition in combination with vemurafenib can prevent emergence of treatment resistant melanoma. This new combination treatment could have the potential to prevent or delay the emergence of treatment-resistant melanoma and prolong the patient’s life.