Signal Transduction Abnormalities as Therapeutic Targets

摘要: The transformation of normal melanocytes to melanoma cells is associated with accumulation genetic alterations that impact directly and/or indirectly on cell cycle regulators. As a result, acquire the ability proliferate and resist apoptosis regardless environmental cues control melanocytes. Although full scope mutations acquired by in their malignant progression has not yet been elucidated, few have identified are regulatory proteins progression. transition self-sufficiency step-wise process, initiated as melanocytic lesions advance from benign dysplastic nevi, primary superficial spreading melanomas, further invasive, nodular metastatic (1,2). This aberrant self-proliferating loop likely play role fixation propagation oncogenic (3). Any mechanism-based approach for therapy requires detailed knowledge critical players maintaining autonomous proliferation. For example, up-regulated activity receptor kinases implicated numerous tumors (4). Prominent this category receptors epidermal growth factor (EGFR) family, such Erb-2 (also called HER or Neu), tyrosine kinase receptor, which overexpressed 20 30% human breast ovarian (5–7). target current future therapeutic strategies (8), use neutralizing antibodies specific inhibitors (4, 9,10). Another example bcr-abl fusion gene, hallmark chronic myelogenous leukemia (CML), encodes constitutively active abl-kinase fused Bcr. A competitive inhibitor Bcr-Abl kinase, STI571(CGP57148), currently one most promising treatments CML (11–15). discovery CGP57148, an effective tumor suppressor specifically CML, serves successful logical mechanistic provides impetus searching signal transduction targets other cancers, including melanomas. In fact, will be described here, investigators pharmaceutical companies already developed several various intermediates factor-mediated signaling, some these compounds clinical trials (4,16,17).