Transformation of normal cells into malignant cells is a multistep process requiring the accumulation of a number of genetic alterations influencing key regulatory processes. In this regard, many types of cancers are diagnosed in the human population with an age-dependent incidence that implicates several events that take the cell from premalignant states into invasive cancers [1
]. Dysregulations may occur in a multitude of pathways and be evidenced through protein mutation, misexpression, or misproccessing, leading to altered functions that confer a pathogenic cell phenotype. While at the cellular level these dysregulations are advantageous in cancer, and may lead to increased survival, at the molecular level, these changes take place at a cost to local energetic stability. To regain a pseudo-stable state, cells co-opt chaperones, for example, Hsp90, to bind aberrant proteins involved in the dysregulated processes with high-affinity and maintain them in a functional conformation [2
]. These interactions buffer the local molecular instability and allow for the accumulation of aberrant proteins that ultimately leads to the blossoming of disease. Thus, following dysregulation in the abundance, stability or activity of a given protein, cell survival can become critically dependent on the association of client proteins of non-native stability with Hsp90.
In cancer, Hsp90 and associated co-chaperones were found to assist in the correct conformational folding of transformation-specific 'client proteins' without significantly binding to, or influencing the folding of, 'normal' protein counterparts; many of these client proteins are signal-transduction regulators of cell growth, differentiation, the DNA damage response, and cell survival [2
]. Small molecule inhibitors of Hsp90 disturb its association with aberrant proteins and stimulate their degradation, a process initiated by recruitment of E3-ligases and mediated by the proteasome [2
Historically, v-Src kinase was the first oncoprotein shown to display unusually stable interactions with Hsp90 and associated chaperones [8
]. In contrast, non-oncogenic c-Src requires only limited assistance from the Hsp90 machinery for its maturation and cellular function. Similarly, stable expression of the mutant, but not wild-type, p53 conformation required tight association of the p53 protein with Hsp90 [9
]. In the chronic myelogenous leukemia cell line K562, transformation is driven by the aberrant fusion of the genes bcr
, leading to the production of a constitutively active kinase, Bcr-Abl. Hsp90, which is minimally required for the stabilization of Abl itself, becomes closely associated with Bcr-Abl and maintains the kinase's functionality in this dysregulated state [10
]. Nucleophosmin-anaplastic lymphoma kinase, found in lymphomas, is another recognized tumor-specific client of Hsp90 [12
], as is mutated Flt3, a kinase involved in driving transformation in acute myeloid leukemias [13
]. Steroid-hormone receptors in breast and prostate cancers have an important role in the malignant behavior of these tumors. They too are examples of tumor-specific clients where oncogenic activity can be disrupted by Hsp90 inhibitors [14
]. Epidermal growth factor receptor harboring kinase-activating mutations that are involved in the transformation of non-small cell lung cancers also associates with Hsp90. An inhibitor of Hsp90 triggers the rapid degradation of these kinases without affecting wild-type epidermal growth factor receptor [16
]. Zeta-chain-associated protein kinase 70 (ZAP-70), expressed in patients with aggressive chronic lymphocytic leukemia (CLL) and required for cell survival and signaling in CLL, behaves as an Hsp90 client protein only in CLL cells [17
]. Examples may be extended to numerous additional transformed cell types but, in sum, multiple proteins involved in cell-specific oncogenic processes have been shown to be tightly regulated by the binding of Hsp90 and undergo selective degradation following treatment with an Hsp90 inhibitor. In this sense, at the phenotypic level, Hsp90 seems to serve as a biochemical buffer for the numerous cancer-specific lesions that are characteristic of diverse tumors.
In an effort to refine the many characteristics that are required for the development of the fully malignant phenotype, Hanahan and Weinberg proposed six essential phenotypic traits, referred to as the 'six hallmarks' of a cancer cell [1
]. Common to these hallmark traits is Hsp90, a protein that has the capacity to regulate key elements of each of these processes, suggesting that the chaperone is an indispensable controller of multiple proteins regulating these cancer hallmarks [1
In summary, malignant cells co-opt Hsp90 to maintain their viability under the pressure of aberrant proteins and, therefore, allow malignant transformation and the facilitation of disease progression. Hsp90 inhibition therefore offers the potential of accomplishing what most targeted anticancer therapies do not: the simultaneous disruption of multiple signaling events critical to all recognized cancer hallmarks. In consequence, the unique biological role of Hsp90 in cancer cells has suggested that its inhibition could be an answer to the challenge imposed on therapy by the heterogeneity and adaptability of cancer cells, and represent a singular therapeutic modality against a large array of tumors.