How Melanoma Cells Evade Chemotherapy
From Melanocytes to Melanoma
Melanomas are intrinsically resistant to both radiotherapy and chemotherapy. Chemotherapy is not a very effective way to treat metastatic melanomas. For this reason, therapy of metastatic melanoma has focused on biological approaches, with some significant recent success in immunotherapy. Still, more effective use of chemotherapy in metastatic melanoma would be a vast improvement in treatment of this disease. The design of chemotherapy to treat melanoma has been a challenging task, because the
... task, because the precise mechanisms of drug resistance in melanoma cells are largely unknown. Moreover, in addition to intrinsic resistance of melanoma to chemotherapy, acquired resistance could be achieved by induction or selection of heterogeneous melanoma cells with a selective growth advantage. The most common cause of multidrug resistance (MDR) in human cancers is the expression of one or more energy-dependent multidrug transporters that efflux anticancer drugs out of cells. Melanoma cells express a cluster of such transporters, which include adenosine triphosphate-binding cassette (ABC)-A9, ABCB1 (MDR1, P-glycoprotein), ABCB5, ABCC1 (multidrug resistance-associated protein-1), and ABCC2 (MRP2/canalicular multispecific organic anion transporter). These transporters may be associated with resistance to a broad range of anticancer drugs in melanomas. In addition, other mechanisms of resistance are also important, including overexpression of inhibitors of apoptosis, altered expression of either oncogenes or tumor suppressors, and drug-detoxifying properties of melanosomes. Defining and circumventing these resistance mechanisms would be a major step toward the ultimate goal of improved treatment of melanomas.