Sustained mutant p53 is required for tumor maintenance and is a therapeutic target in vivo.

  • Major finding: Sustained mutant p53 is required for tumor maintenance and is a therapeutic target in vivo.

  • Clinical relevance: Targeting HSP90-mediated stabilization of mutant p53 inhibits tumor growth and prolongs survival.

  • Impact: Exploiting tumor dependence on gain-of-function mutant p53 may be an effective therapeutic strategy.

Missense mutations in the tumor suppressor TP53 are frequently expressed in human tumors and result in constitutive stabilization of gain-of-function oncogenic mutant p53 proteins within tumors. To assess whether destabilization of mutant p53 is an effective therapeutic strategy in vivo, Alexandrova, Yallowitz, and colleagues generated a mouse model with conditional inactivation of mutant Trp53R248Q, a hotspot mutation present in many sporadic cancers and associated with Li–Fraumeni syndrome. Li–Fraumeni patients born with this mutation show accelerated tumor onset, higher tumor numbers, and shorter tumor-free survival compared with Li–Fraumeni patients with p53 loss. Ablation of mutant p53 suppressed the growth of allograft T-cell lymphomas and extended survival, indicating that sustained expression of stabilized mutant p53 is necessary for tumor maintenance. Consistent with this idea, genetic inactivation of mutant Trp53R248Q induced regression or stagnation of autochthonous tumors due to increased apoptosis and inhibited lung metastasis, resulting in significantly longer median overall and T-cell lymphoma–specific survival. Pharmacologic inhibition of the HSP90 chaperone and its positive regulator histone deacetylase 6, which are overexpressed in tumors and required for stabilization of mutant p53, via combined treatment with 17DMAG and SAHA prevented T-cell lymphoma formation and prolonged survival in mutant Trp53R172H/R172H mice, but not Trp53-null mice, suggesting that, in a mutant p53 context, the efficacy of HSP90 inhibition is largely dependent on destabilization of mutant p53 protein. Similarly, single-agent long-term treatment with the more potent HSP90 inhibitor ganetespib specifically destabilized mutant p53 and triggered apoptosis in mutant p53–expressing T-cell lymphoma cells, which resulted in suppression of T-cell lymphoma formation and prolonged survival in both Trp53R248Q/− and Trp53R172H/R172H mice, but not Trp53-null mice. These findings underscore the dependence of tumors on sustained expression of gain-of-function mutant p53 and suggest destabilization of mutant p53 protein via targeted inhibition of HSP90 as a potential therapeutic strategy.

Alexandrova EM, Yallowitz AR, Li D, Xu S, Schulz R, Proia DA, et al. Improving survival by exploiting tumour dependence on stabilized mutant p53 for treatment. Nature 2015 May 25 [Epub ahead of print].

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