TY  - JOUR
AU  - Isermann, Tamara
AU  - Schneider, Kim Lucia
AU  - Wegwitz, Florian
AU  - De Oliveira, Tiago
AU  - Conradi, Lena-Christin
AU  - Volk, Valery
AU  - Feuerhake, Friedrich
AU  - Papke, Björn
AU  - Stintzing, Sebastian
AU  - Mundt, Bettina
AU  - Kühnel, Florian
AU  - Moll, Ute M
AU  - Schulz-Heddergott, Ramona
TI  - Enhancement of colorectal cancer therapy through interruption of the HSF1-HSP90 axis by p53 activation or cell cycle inhibition.
JO  - Cell death and differentiation
VL  - nn
SN  - 1350-9047
CY  - [London]
PB  - Springer Nature
M1  - DKFZ-2025-00751
SP  - nn
PY  - 2025
N1  - epub
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:40204953
DO  - DOI:10.1038/s41418-025-01502-x
UR  - https://inrepo02.dkfz.de/record/300301
ER  -