Targeting the Cell Cycle and p53 in Combination with BRAF-Directed Therapy

The incidence of melanoma continues to increase with the vast majority of skin cancer-related deaths attributable to melanoma. Historically, response rates for systemic treatments for metastatic melanoma were only 5–20 % for chemotherapy, and the prognosis of patients with metastatic disease was extremely poor. The discovery of BRAF mutations in melanoma led to the development of BRAF-directed therapy which dramatically increased response rates. However, most patients treated with BRAF inhibitors eventually show disease recurrence, and it is now believed that combination therapies based upon a BRAF inhibitor backbone is the therapeutic future. Appropriate regulation of the cell cycle is critical for preventing progression to cancer, however the vast majority of melanomas harbor alterations in cell cycle and p53 regulatory pathways such as loss of CDKN2A and overexpression of CDK4, cyclin D1, MDM2 and MDM4. The alterations in these pathways appear to play critical roles in the development of melanoma and may represent potential therapeutic targets. Furthermore, some studies suggest that there is interaction between BRAF, key cell cycle proteins and the p53 pathway and that BRAF inhibitors may synergize with treatments that either enhance p53 function or inhibit CDK activity. Preclinical studies in melanoma have shown the potential efficacy of enhancing p53 function through inhibition of MDM2 or MDM4. Other studies have shown potential benefit in antagonizing CDK activity through use of small molecule inhibitors. However, targeting p53 and CDK function in melanoma is at an early stage and additional studies are needed particularly to understand the effects of combining these therapies with BRAF inhibition. Furthermore, clinical trials testing these therapeutic combinations specifically in melanoma patients are also needed to determine if the results of preclinical studies can be translated into beneficial effects in humans.