The Myb-p300 Interaction Is a Novel Molecular Pharmacologic Target

摘要

There are large and growing numbers of molecularly targeted agents under study in oncology. Yet, the nature of the pathways targeted in the cancer clinic should be broadened (1). Success stories include the discoveries of antagonists that affect growth factor receptors and enzymes that are either overexpressed or mutated relative to their normal counterparts. These proteins function as oncogenic changes that drive the growth, survival, or abnormal differentiation state of a specific cancer. Clinical examples of this include HER2-targeted treatments of breast cancer (2), inhibitors of BRAF in melanoma (3), or antagonists of the epidermal growth factor receptor (EGFR) and its tyrosine kinase in lung cancer (4), to cite a few of many possible ones. However, most cancers diagnosed in patients do not harbor such alterations. Hence, other biochemical pathways that interfere with aberrant growth of cancers must be found. One way to expand the spectrum of such targets is to disrupt protein-protein interactions. This is the case when cancers depend on them for their growth, maturation, or survival. Promising antineoplastic strategies would then be uncovered. Indeed, targets once considered intractable would become exposed. This is why the study by Uttarkar and colleagues (5) is noteworthy. They revealed a way to interfere with the oncogenic effects of one of the earliest known oncogenes, Myb (6). This oncogene was previously considered an unattractive pharmacologic target. They accomplished the feat of showing that Myb is amenable to interference by exploiting a critical c-Myb protein-protein interaction. This builds on prior work that showed Myb-dependent gene expression was inhibited by the sesquiterpene lactone mexicanin-1 (7).