Hsp90 is one among a small group of proteins collectively known as “heat shock proteins.” Hsp class proteins act as molecular “chaperones” that guide protein folding and guard against inappropriate protein interactions. In normal cellular operations, they help prevent protein misfolding due to external and internal stressors, such as heat, acidosis, heavy metals, and hypoxia.1
Cancer subverts the normal operation of hsp’s, using them to promote malignant cell growth. Cancer cells express higher levels of heat shock proteins, reflecting their effort to maintain homeostasis in a hostile environment. Researchers have shown that in addition to aiding the survival of tumor cells, heat shock proteins also promote translational alterations because they guide DNA metabolic processes. Pharmaceutical researchers have been targeting several heat shock proteins as a means to destabilize malignant cell reproduction to halt cancer progression.
The chaperone Hsp90 has received significant attention because the many client proteins it guides are involved in cell growth, development, and survival — all of which are disregulated in cancer. Over the last 10 years, several small molecule strategies for Hsp90 inhibition have shown potential efficacy, but the complexity of the chaperone system and its far-reaching effects on many other cellular systems have proven difficult to manage from a drug-delivery point of view. 2,3
A recent study applied quantitative proteomics using mass spectrometry to study the effects of the Hsp90 inhibitor 17-DMAG across all proteins. Using the HeLa cell line, the researchers mapped the entire proteome in response to 17-DMAG. In addition to corroborating the findings of other studies that Hsp90 regulates DNA metabolic processes, they also found that a large number of protein kinases are clients of Hsp90.2 This is interesting because cancer drug therapies based on tyrosine kinase inhibitors have been used successfully to encourage apoptosis in cancer cells. The problem is that they are prone to resistance over time. The researchers speculate that perhaps the two drug classes working together would improve efficacy and limit resistance. The theory is that when 17-DMAG downregulates Hsp90, cancer cell kinases can no longer harness the heat shock system to promote malignant growth, which is how they were developing resistance to the kinase inhibitors.2
While this important finding shows promise, we still need to delve more deeply into the function of Hsp90 and the entire chaperone machinery, for the same study found significant negative impacts that would run counter to cancer treatment. For example, 17-DMAG downregulates LRIG1, a tumor suppressor. LRIG1 downregulation is a hallmark of renal carcinoma and breast cancers.2 Similarly, tumor antigen L6, which regulates angiogenesis and is associated with tumor cells, is upregulated in response to the Hsp90 blocker.3
Researchers are slowly uncovering a complete picture of all of the interactions and roles that heat shock proteins and Hsp90 in particular plays. The path to drug discovery, however, is long and circuitous. Advances in the technologies required to understand systems-wide impact of proteins across time and space are critical to refining our approach to engineering therapeutics based on inhibitor, cell line, cancer type, disease state, comorbidities, and many other factors yet unexplored.
1. Whitesell, L. and Lindquist, S.L. (2005) ‘Hsp90 and the chaperoning of cancer‘, Nature Reviews Cancer, 5 (10), (pp. 760-772)
2. Sharma, K., et al. (2012) ‘Quantitative proteomics reveals that hsp90 inhibition preferentially targets kinases and the DNA damage response‘, Molecular & Cellular Proteomics, 11 (3), (pp. 1-12)
3. Cheung, C.H., et al. (2010) ‘Targeting Hsp90 with small molecule inhibitors induces the over-expression of the anti-apoptotic molecule, survivin, in human A549, HONE-1 and HT-29 cancer cells‘, Molecular Cancer, 9 (77), (pp. 1-11)