HSP90 inhibition is most effective when combined with HSF1-targeted treatments.

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In the realm of cancer research, many potential targets have come to the forefront for scientific investigators.  Some targets are specific genes leading to specific cancers and some are regularly occurring proteins that get high-jacked when cancer takes root, across a broad spectrum of cancers.  HSP90 is one such target from the latter.  HSP90 is an important trafficking and chaperone protein, pivotal for cancer survival.  HSP90 inhibitors like Geldanamycin, its derivative 17-AAG, and the new Ganetespib from Synta Pharmaceuticals are some examples thereof.  Unfortunately, it seems that some cancers can become acclimatized to these drugs and find some way to overcome them.  In “Targeting HSF1 sensitizes cancer cells to HSP90 inhibition” published in April 2013 in Oncotarget by researchers at Novatris Institutes in Cambridge, MA and Emeryville, CA, the development of “resistance” to these HSP90 inhibitors in some cancers has been considered.

HSF1, a transcription factor normally involved in the heat shock response (upstream of HSP70 and HSP90), is hyper-activated in many cancers as the signalling, metabolism and translational cellular machinery gets reorganized to support the oncogenic activities.  Silencing or inactivating HSF1 has been shown to suppress tumour growth.  In this study, the researchers have shown that HSF1 is a sensitizer to HSP90 inhibition; allowing the cell to overcome therapies aimed at HSP90 inhibition in some cases.  When HSP90 inhibitors were used in conjunction with “deactivated” HSF1 in cancer cells, the results confirmed their suspicions: targeting and inactivating both HSP90 and HSF1 is a more robust approach to attenuating cancer development and progression.

In an attempt to understand the mechanism at play, the researchers managed to identify the HSF1 target gene DEDD2, which led to a decrease in the potency of the HSP90 inhibitors.  This confirms that HSF1 does indeed provide a way for cancer cells to overcome HSP90 inhibition through a feedback mechanism.  Though much more needs to be elucidated in terms of cofactors and other molecules at play, the researchers conclude that combining HSP90 inhibitors with a reagent that targets and controls HSF1 activity could prove to be a better method to attack cancer through the homeostatic machinery.

The original research paper was published in: Oncotarget (April 2013)

“Targeting HSF1 sensitizes cancer cells to HSP90 inhibition”

Antibodies for HSF1, HSP70, Erk and HSP90 were used in this experiment. StressMarq offers all of these antibodies in both unconjugated and conjugated formats.