HER-2/neu and topoisomerase IIalpha—simultaneous drug targets in cancer

Tero A H Järvinen, Edison T Liu
Combinatorial Chemistry & High Throughput Screening 2003, 6 (5): 455-70
In solid tumors the predominant genetic mechanism for oncogene activation is through amplification of genes. The HER-2 (also known as ErbB2/c-erbB2/HER-2/neu) oncogene is the most frequently amplified oncogene in breast cancer and is also commonly amplified in other forms of cancer. Alongside its important role in tumor induction, growth and progression, HER-2 is also a target for a new form of chemotherapy. Since 1998, breast cancer patients have been treated with considerable success with Herceptin (trastuzumab), a recombinant antibody designed to block signaling through the HER-2 receptor. In addition to Herceptin, a large number of various HER-2 directed immunological and genetic approaches, either targeting the HER-2 receptor, its signaling pathways or both HER-2 and epidermal growth factor receptor (EGFR) together, have demonstrated promising pre-clinical potential towards HER-2 amplified carcinomas. Moreover, the HER-2 amplicon contains other genes with altered copy numbers that could be used as targets for chemotherapy. The topoisomerase IIalpha (topoIIalpha) gene (TOP2A) is located adjacent to the HER-2 oncogene at the chromosome location 17q12-q21 and is either amplified or deleted, with equal frequency, in almost 90% of HER-2 amplified primary breast tumors. Recent data suggest that amplification or deletion of TOP2A may account for both sensitivity or resistance to topoII-inhibitor-chemotherapy, depending on the specific genetic defect at the TOP2A locus. The understanding of HER-2 amplification and its role in the pathogenesis of cancer is expanding. The number of therapeutic strategies targeting HER-2 signaling pathways will most probably be introduced in the treatment of HER-2 amplified tumors within the next few years. Combining HER-2 targeting therapies with conventional forms of cytotoxic chemotherapy, where additional diagnostics tests such as those ascertaining topoIIalpha status, may be helpful for the ideal selection of patients for the combination therapy of a HER-2 targeting drug together with a cytotoxic drug. The clinical and therapeutic importance of the HER-2 and TOPO2A status of tumor cells in cancer management will only increase within the next few years.

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