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• W4384206807 abstract "The tumor suppressor p53 (TP53) is mutated in ~70 % of colorectal cancer (CRC) cases. Of these cases, approximately 80 % undergo subsequent p53 loss-of-heterozygosity (p53LOH), losing the remaining wildtype p53 (WTp53) allele. In case of gain-of-function (GOF) p53 mutants, the tumors stabilize the mutant p53 (mutp53) protein and thus acquire new tumorigenic functions upon p53LOH, to enhance their aggressive phenotype. Full understanding of the driving forces behind this p53LOH, and why it is the gatekeeper to mutp53 stabilization to enhance tumorigenesis, remains elusive. To gain improved understanding on the connection between p53LOH and mutp53 stabilization and how it enhancestumorigenesis, we studied the implications of p53 on the chaperone system. We identified a novel p53 tumor suppressive function. P53 has an inhibitory function on the major transcription factor of the chaperone system, heat shock factor 1 (HSF1), the only system known so far to stabilize mutp53. This inhibitory function of WTp53 acts through the downstream factors CDKN1A/p21 – CDK4/6 – E2F – MLK3 – MAPK. As such, only upon loss of WTp53, solid tumors stabilize the mutp53 protein, and enhance their aggressive nature. The suppression of HSF1 by WTp53, in a heterozygous background, acts as one selection pressure for p53LOH and highlights one plausible reason why the heterozygous p53 state is only a transient state in tumors. Based on the WTp53 – p21 – CDK4/6 – HSF1 inhibitory axis, we suggested a new HSP90-based combination therapy. HSP90 inhibitors have failed to progress into the clinics due to the induction of the heat shock response (HSR) and the associated upregulation of stress-inducible chaperones, which may stabilize tumor-driving proteins. However, due to their tumor selectivity, their clinical interest remains high. We demonstrate that the activation of WTp53 suppresses the HSR in CRC cell lines and murine tumor-derived colonic organoids induced by HSP90 inhibitors. Additionally the combination of p53 activation with HSP90 inhibition results in strong tumor regression in vivo. Similarly, a combination of HSP90 inhibitors with CDK4/6 inhibition shows synergistic reduction in cell viability of WTp53 and mutp53 cells as well as enhanced HSP90 client degradation. Our findings highlight the importance of WTp53 in tumor suppression, with its loss allowing increased activation of the chaperone system and subsequent mutant protein stabilization. Targeting the WTp53-HSF1 pathway in combination with HSP90 carries strong potential for cancer therapy especially due to the tumor selectivity of HSP90 inhibitors." @default.
• W4384206807 created "2023-07-14" @default.
• W4384206807 creator A5081709800 @default.
• W4384206807 date "2023-07-13" @default.
• W4384206807 modified "2023-09-24" @default.
• W4384206807 title "Modulation of HSF1 activity by p53 and its impact in cancer therapies" @default.
• W4384206807 doi "https://doi.org/10.53846/goediss-9996" @default.
• W4384206807 hasPublicationYear "2023" @default.
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