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Mutation of the co-chaperone Tsc1 in bladder cancer diminishes Hsp90 acetylation and reduces drug sensitivity and selectivity

The researchers have recently identified the tumour suppressor tuberous sclerosis complex 1 as a new co-chaperone of Hsp90 that affects Hsp90 binding to its inhibitors.

Their findings have been published in the journal Oncotarget

These results suggest that TSC1 status may predict response to Hsp90 inhibitors in patients with bladder cancer, and co-targeting HDACs can sensitise tumours with Tsc1 mutations to Hsp90 inhibitors.

Dr Mehdi Mollapour and Dr Dimitra Bourboulia said: "Over 80,000 people will be diagnosed with bladder cancer and approximately 18,000 patients will die from this disease in the United States in 2019."

Tsc1 assists in the deceleration of Hsp90 ATPase activity and the Hsp90 chaperone cycle, and Tsc1 expression increases Hsp90 binding to its inhibitors.

Mutation and inactivation of the tumour suppressor TSC1 has been found in approximately 15 percent of bladder cancers and loss of heterozygosity of a region spanning the TSC1 locus at 9q34 has been seen in roughly 54 percent of bladder cancers.

The authors therefore hypothesised that mutation and inactivation of TSC1 in bladder cancer cells leads to decreased sensitivity to Hsp90 inhibitors.

Their data supported this hypothesis, and we mechanistically demonstrated that mutation and loss of TSC1 in bladder cancer cells causes hypoacetylation of Hsp90-K407/K419 and subsequent decreased binding of Hsp90 to its inhibitor ganetespib.

Their results suggest that Tsc1 status can predict response to Hsp90 inhibition in bladder cancer patients and further provide a strategy to co-target HDACs and Hsp90 in bladder cancers with mutation in TSC1.

The research team concluded: "This also reduces the sensitivity of bladder cancer cells to the Hsp90 inhibitors. Additionally, in those patients with TSC1 mutated bladder cancer, inhibition of HDACs can potentially restore Hsp90 acetylation and sensitivity to Hsp90 inhibitors."

Source: Oncotarget / Impact Journals LLC

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