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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: UNLABELLED. Meshes: Animals, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Female, HSP70 Heat-Shock Proteins, HSP90 Heat-Shock Proteins, Heat-Shock Response, Humans, Lung Neoplasms, Male, Mice, Mice, SCID, Phosphatidylinositol 3-Kinases, Random Allocation, Signal Transduction, TOR Serine-Threonine Kinases, Triazoles, Up-Regulation, Xenograft Model Antitumor Assays.
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Does mTOR inhibition potentiate HSP90 inhibitor activity via cessation of HSP synthesis? Context: Because of their pleiotropic effects on critical oncoproteins, inhibitors of HSP90 represent a promising new class of therapeutic agents for the treatment of human cancer. However, pharmacologic inactivation of HSP90 subsequently triggers a heat shock response that may mitigate the full therapeutic benefit of these compounds. To overcome this limitation, a clinically feasible method was sought to block HSP synthesis induced by the potent HSP90 inhibitor ganetespib. An immunoassay screen of 322 late-stage or clinically approved drugs was performed to uncover compounds that could block upregulation of the stress-inducible HSP70 that results as a consequence of HSP90 blockade. Interestingly, inhibitors of the phosphoinositide 3-kinase (PI3K)/mTOR class counteracted ganetespib-induced HSP70 upregulation at both the gene and protein level by suppressing nuclear translocation of heat shock factor 1 (HSF1), the dominant transcription factor controlling cellular stress responses. This effect was conserved across multiple tumor types and was found to be regulated, in part, by mTOR-dependent translational activity. Pretreatment with cycloheximide, PI3K/mTOR inhibitor, or an inhibitor of eIF4E (a translation initiation factor and downstream effector of mTOR) all reduced ganetespib-mediated nuclear HSF1 accumulation, indicating that mTOR blockade confers a negative regulatory effect on HSF1 activity. Moreover, combined therapy regimens with mTOR or dual PI3K/mTOR inhibitors potentiated the antitumor efficacy of ganetespib in multiple in vivo models.
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Collectively these data identify a novel strategy to optimize the therapeutic potential of HSP90 inhibitors. Final Decision: yes