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

Abstract

The molecular chaperone Heat shock protein 90 (Hsp90) is essential for the folding, stability, and activity of several drivers of oncogenesis. Hsp90 inhibitors are currently under clinical evaluation for cancer treatment, however their efficacy is limited by lack of biomarkers to optimize patient selection. We have recently identified the tumor suppressor tuberous sclerosis complex 1 (Tsc1) as a new co-chaperone of Hsp90 that affects Hsp90 binding to its inhibitors. Highly variable mutations of TSC1 have been previously identified in bladder cancer and correlate with sensitivity to the Hsp90 inhibitors. Here we showed loss of TSC1 leads to hypoacetylation of Hsp90-K407/K419 and subsequent decreased binding to the Hsp90 inhibitor ganetespib. Pharmacologic inhibition of histone deacetylases (HDACs) restores acetylation of Hsp90 and sensitizes Tsc1-mutant bladder cancer cells to ganetespib, resulting in apoptosis. Our 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.

Mutational Landscape and Environmental Effects in Bladder Cancer

“…Loss of TSC1 leads to hypoacetylation of Heat shock protein 90 (Hsp90) and subsequent decreased binding to the Hsp90 inhibitor [ 43 ]. Combined Hsp90/mTOR (mammalian target of rapamycin) inhibition is a promising therapeutic approach for TSC1 -mutant bladder cancer [ 44 ].…”

Identification of Hsp90 inhibitors as potential drugs for the treatment of TSC1/TSC2 deficient cancer

“…They also studied a syngeneic orthotopic model of HCC, using a mouse HCC cell line, Hepa129. In that model, the rapamycin - 17-DMAG combination showed a dramatic synergistic effect in reducing tumor volume (69). There are many differences between this study and ours reported here, including different cell lines, different agents and doses being studied, and use of a syngeneic orthotopic model, that may explain these distinct results.…”

“…Mollapour and colleagues reported that TSC1 was a co-chaperone of HSP90, facilitating HSP90 function to enhance proper folding of client proteins, including TSC2 (68). They then went on to show that loss of TSC1 leads to reduced acetylation of HSP90 at K407/K419, which leads to decreased binding by ganetespib; and that inhibition of histone deacetylases with concurrent ganetespib treatment led to enhanced growth suppression of RT4, a TSC1 null bladder cancer cell line (69).…”

“…In addition, the combination of rapamycin and HSP90 inhibitors has been previously studied for treatment of hepatocellular cancer (HCC) (69). Lang et al reported that the combination of rapamycin and 17-(dimethylaminoethylamino)-17-demethoxygeledanamycin (17-DMAG), an HSP90 inhibitor, had a greater effect than either drug alone in reducing the growth rate of Huh-7 cells, an HCC cell line, in a subcutaneous xenograft model (69). However, the difference in comparison to single drug treatments was modest, and the combination reduced tumor growth without causing reduction in tumor size.…”

“…and that inhibition of histone deacetylases with concurrent ganetespib treatment led to enhanced growth suppression of RT4, a TSC1 null bladder cancer cell line (69).…”