Mechanistic understanding of post-translational regulation of the Hsp90 molecular chaperone machinery

Heat shock protein 90 (Hsp90) is an essential molecular chaperone that cancer cells utilise to protect over-expressed or mutated oncoproteins from misfolding and degradation. Hsp90 is recognised as a crucial facilitator of “oncogene addiction” and cancer cell survival. Hsp90 chaperone function is coupled to its ATPase activity, which can be inhibited by natural products including geldanamycin and radicicol. There are currently 19 Hsp90 inhibitors in various stages of clinical trial for cancer patients.
Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin) has been promising in certain cases in which the tumor is driven by a highly Hsp90-dependent client protein (e.g., HER2-positive breast cancer or EML4-ALK-positive non-small cell lung cancer). However, in most cases single agent Hsp90 inhibitors have proven to be less efficacious than expected. This can be attributed to (a) Hsp90 participation in numerous pro-survival signaling pathways and (b) Hsp90 inhibition frequently leads to cytostasis and not cytotoxicity. Therefore, novel strategies to enhance tumor cell hypersensitivity to Hsp90 inhibitors are being actively sought, including combination therapies with synergistic effects.
This PhD project will use both yeast and mammalian cancer cells and various molecular and cell biology methods to elucidate how post-translational modification of Hsp90 and its co-chaperones work in concert to regulate the chaperone function.
The ultimate goal is to exploit this information towards new therapeutic strategies and enhance the efficacy of current Hsp90 inhibitors in the clinic.