Linking hsp90's role as an evolutionary capacitator to the development of cancer.

This paper links Heat Shock Protein Hsp90 as an evolutionary capacitator with the development of cancer. Hsp90 stabilises proteins associated with cancer in a number of ways. Canalisation allows for the accumulation of malignant mutations in the genome, and selection of beneficial phenotypes when cancer cells are stressed, allowing oncogenic development and progression. Hsp90 may allow for mutational 'big bangs' that can trigger primary malignant transformation. Hsp90 buffers catastrophic mutations in the oncogenome to prevent protein degradation and cellular apoptosis. Hsp90 was found to prevent the degradation of mutated p53, encouraging uncontrolled proliferation of cancer cells. Hsp90 buffering of mutations in response to cytotoxic therapy can lead to expression of beneficial phenotypes when Hsp90 is supressed and development of drug resistance. Trials with Hsp90 inhibitors have shown some success as an adjunctive therapy in preventing cancer progression, development of drug resistance, and even re-sensitisation to therapy after chemoresistance has developed.