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

The cover for issue 56 of Oncotarget features Figure 5, “HDAC inhibition synergizes with Hsp90 inhibition to induce apoptosis in bladder cancer.,” Woodford, et al.

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

Their findings suggest that TSC1 status may predict response to Hsp90 inhibitors in patients with bladder cancer, and co-targeting HDACs can sensitize tumors 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 tumor suppressor TSC1 has been found in approximately 15% of bladder cancers and loss of heterozygosity of a region spanning the TSC1 locus at 9q34 has been seen in roughly 54% of bladder cancers.

The authors therefore hypothesized 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 Mallapour/Bourboulia 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.”

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Correspondence to – Mehdi Mollapour –

[email protected]

and Dimitra Bourboulia –

[email protected]

Keywords – tuberous sclerosis complex (TSC), Tsc1 (Hamartin), Tsc2 (Tuberin), heat shock protein (Hsp90), bladder cancer

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