Overcoming melanoma drug resistance through metabolic targeting?

future clinical trial development. First, melanoma subpopulations remaining after MTX/TMECG treatment could eventually acquire resistance, as commonly occurs with many targeted therapies. This is especially concerning because the tumor burden observed following combination therapy is significantly reduced, but not completely eradicated. To address issues of potential therapeutic resistance, Saez-Ayala et al. dissociated luciferase-tagged B16/ F10 tumors cells from vehicle or MTX/ TMECG-treated mice to investigate their continued sensitivity to MTX/ TMECG treatment in vitro. Strikingly, cells harvested from both vehicle and MTX/TMECG-treated mice were equally sensitive to the combination therapy in culture. However, it still remains to be seen whether melanoma cells can escape MTX/TMECG-induced apoptosis in vivo following prolonged treatment. Second, the authors addressed a potential concern over the toxicity that MTX/ TMECG may have on surrounding tissues. The goal of this combination therapy is to specifically target the death of MITF-expressing melanoma cells; however, there are non-melanoma MITF-expressing cells in the body (e.g., pigmented eye epithelial cells, skin melanocytes) that could be susceptible to TMECG-induced apoptosis. However, the authors observed no deleterious effects of MTX/TMECG on the integrity of skin melanocytes or pigmented epithelial cells of the eye following extended exposure to MTX and TMECG. This is most likely because depletion of dTTP should only affect proliferating cells; the RPE and differentiated melanocytes in the skin and hair follicle are non-proliferating. This same dosing schedule also caused no weight loss in the treated mice. As the human species continues to evolve, so do the complexities of the diseases we suffer from. Drug resistance has been a long-standing impediment in our battle against melanoma, as well as many other malignancies. Decades ago, we learned that cancer cells can respond to initially efficacious chemotherapy with a multidrug resistant phenotype (e.g., through amplification of MDR1). More recently, tumors were found to recur after highly effective molecularly targeted therapies, often through secondary mutations in the same gene, or in associated pathway members. The extensive cellular heterogeneity of many tumors is thought to be responsible for much of the observed acquired resistance. In this report, Saez-Ayala and colleagues switch from the popular targeted approach by introducing a novel bi-modal, differentiation-based therapy that first attempts to homogenize tumor heterogeneity, followed by treatment with a drug that specifically targets the newly differentiated tumor cells. This two-step therapeutic strategy has the potential to revolutionize the manner in which we treat drug-resistant cancers. Ultimately, most of the functions of tumor cells rely on hardwired pathways that were part and parcel of the normal cells from which they originated. Perhaps exploiting these same hardwired pathways, such as differentiation, will be key to future therapeutic breakthroughs, keeping us a step ahead of the ever-evolving tumor.