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@ARTICLE{Isermann:300301,
      author       = {T. Isermann$^*$ and K. L. Schneider and F. Wegwitz and T.
                      De Oliveira and L.-C. Conradi and V. Volk and F. Feuerhake
                      and B. Papke$^*$ and S. Stintzing$^*$ and B. Mundt and F.
                      Kühnel and U. M. Moll and R. Schulz-Heddergott},
      title        = {{E}nhancement of colorectal cancer therapy through
                      interruption of the {HSF}1-{HSP}90 axis by p53 activation or
                      cell cycle inhibition.},
      journal      = {Cell death and differentiation},
      volume       = {nn},
      issn         = {1350-9047},
      address      = {[London]},
      publisher    = {Springer Nature},
      reportid     = {DKFZ-2025-00751},
      pages        = {nn},
      year         = {2025},
      note         = {epub},
      abstract     = {The stress-associated chaperone system is an actionable
                      target in cancer therapies. It is ubiquitously upregulated
                      in cancer tissues and enables tumorigenicity by stabilizing
                      oncoproteins. Most inhibitors target the key component,
                      heat-shock protein 90 (HSP90). Although HSP90 inhibitors are
                      highly tumor-selective, they fail in clinical trials. These
                      failures are partly due to interference with a negative
                      regulatory feedback loop in the heat-shock response (HSR):
                      in response to HSP90 inhibition, there is compensatory
                      synthesis of stress-inducible chaperones, mediated by the
                      transcription factor heat-shock-factor 1 (HSF1). We recently
                      identified that wild-type p53 reduces the HSR by repressing
                      HSF1 via a p21-CDK4/6-MAPK-HSF1 axis. Here, we test whether
                      in HSP90-based therapies, simultaneous p53 activation or
                      direct cell cycle inhibition interrupts the deleterious
                      HSF1-HSR axis and improves the efficiency of HSP90
                      inhibitors. We found that the clinically relevant p53
                      activator Idasanutlin suppresses the HSF1-HSR activity in
                      HSP90 inhibitor-based therapies. This combination
                      synergistically reduces cell viability and accelerates cell
                      death in p53-proficient colorectal cancer (CRC) cells,
                      murine tumor-derived organoids, and patient-derived
                      organoids (PDOs). Mechanistically, upon combination therapy,
                      CRC cells upregulate p53-associated pathways, apoptosis, and
                      inflammatory pathways. Likewise, in a CRC mouse model, dual
                      HSF1-HSP90 inhibition represses tumor growth and remodels
                      immune cell composition. Importantly, inhibition of the
                      cyclin-dependent kinases 4/6 (CDK4/6) under HSP90 inhibition
                      phenocopies synergistic repression of the HSR in
                      p53-proficient CRC cells. Moreover, in p53-deficient CRC
                      cells, HSP90 inhibition in combination with CDK4/6
                      inhibitors similarly suppresses the HSF1-HSR and reduces
                      cancer growth. Likewise, p53-mutated PDOs respond to dual
                      HSF1-HSP90 inhibition, providing a strategy to target CRC
                      independent of the p53 status. In sum, we provide new
                      options to improve HSP90-based therapies to enhance CRC
                      therapies.},
      cin          = {BE01},
      ddc          = {610},
      cid          = {I:(DE-He78)BE01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40204953},
      doi          = {10.1038/s41418-025-01502-x},
      url          = {https://inrepo02.dkfz.de/record/300301},
}