Heat shock protein 90

热休克蛋白90 热休克蛋白 Hsp90抑制剂 癌症研究 CDC37型 癌细胞 蛋白激酶B 癌症 信号转导 医学 生物 细胞生物学 生物化学 遗传学 基因
作者
Len Neckers,S. Percy Ivy
出处
期刊:Current Opinion in Oncology [Lippincott Williams & Wilkins]
卷期号:15 (6): 419-424 被引量:397
标识
DOI:10.1097/00001622-200311000-00003
摘要

Purpose of review Heat shock protein 90 (Hsp90) is a molecular chaperone required for the stability and function of a number of conditionally activated and/or expressed signaling proteins, as well as multiple mutated, chimeric, or overexpressed signaling proteins, which promote cancer cell growth or survival or both. Hsp90 inhibitors, by interacting specifically with a single molecular target, cause the inactivation, destabilization, and eventual degradation of Hsp90 client proteins, and they have shown promising antitumor activity in preclinical model systems. One Hsp90 inhibitor, 17-AAG, has completed Phase I clinical trial, and several Phase II trials are in progress. Hsp90 inhibitors are unique in that, although they are directed towards a specific molecular target, they simultaneously inhibit multiple signaling pathways that frequently interact to promote cancer cell survival. Recent findings Recently identified clients of Hsp90 participate, frequently in overlapping pathways, in mediating cancer cell survival. These include Akt, Her2, and HIF-1α. Thus, by inhibiting multiple survival pathways used by cancer cells, combination of an Hsp90 inhibitor with standard chemotherapeutic agents may dramatically increase the in vivo efficacy of the standard agent. Furthermore, Hsp90 modulates androgen receptor activity and the activity of several mutated kinases characteristic of several leukemias and lymphomas, making Hsp90 inhibition an attractive modality in these cases. Summary Hsp90 inhibitors may circumvent the characteristic genetic plasticity that has allowed cancer cells to eventually evade the toxic effects of most molecularly targeted agents. The mechanism-based use of Hsp90 inhibitors, both alone and in combination with other drugs, should augment the treatment of multiple forms of cancer.
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