Cancer cell-selective induction of mitochondrial stress and immunogenic cell death by PT-112 in human prostate cell lines

Soler-Agesta, R. (Universidad de Zaragoza) ; Moreno-Loshuertos, R. (Universidad de Zaragoza) ; Yim, C. Y. ; Congenie, M. T. ; Ames, T. D. ; Johnson, H. L. ; Stossi, F. ; Mancini, M. G. ; Mancini, M. A. ; Ripollés-Yuba, C. (Universidad de Zaragoza) ; Marco-Brualla, J. ; Junquera, C. (Universidad de Zaragoza) ; Martínez-De-Mena, R. ; Enríquez, J. A. ; Price, M. R. ; Jimeno, J. ; Anel, A. (Universidad de Zaragoza)

Resumen: PT-112 is a novel immunogenic cell death (ICD)-inducing small molecule currently under Phase 2 clinical development, including in metastatic castration-resistant prostate cancer (mCRPC), an immunologically cold and heterogeneous disease state in need of novel therapeutic approaches. PT-112 has been shown to cause ribosome biogenesis inhibition and organelle stress followed by ICD in cancer cells, culminating in anticancer immunity. In addition, clinical evidence of PT-112-driven immune effects has been observed in patient immunoprofiling. Given the unmet need for immune-based therapies in prostate cancer, along with a Phase I study (NCT#02266745) showing PT-112 activity in mCRPC patients, we investigated PT-112 effects in a panel of human prostate cancer cell lines. PT-112 demonstrated cancer cell selectivity, inhibiting cell growth and leading to cell death in prostate cancer cells without affecting the non-tumorigenic epithelial prostate cell line RWPE-1 at the concentrations tested. PT-112 also caused caspase-3 activation, as well as stress features in mitochondria including ROS generation, compromised membrane integrity, altered respiration, and morphological changes. Moreover, PT-112 induced damage-associated molecular pattern (DAMP) release, the first demonstration of ICD in human cancer cell lines, in addition to autophagy initiation across the panel. Taken together, PT-112 caused selective stress, growth inhibition and death in human prostate cancer cell lines. Our data provide additional insight into mitochondrial stress and ICD in response to PT-112. PT-112 anticancer immunogenicity could have clinical applications and is currently under investigation in a Phase 2 mCRPC study.

Idioma: Inglés

DOI: 10.1186/s12967-024-05739-x

Año: 2024

Publicado en: Journal of translational medicine 22, 1 (2024), 927 [17 pp.]
ISSN: 1479-5876

Financiación: info:eu-repo/grantAgreement/ES/MICINN/PID2019-105128RB-I00

Tipo y forma: Article (Published version)

Área (Departamento): Area Histología (Dpto. Anatom.Histolog.Humanas)
Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)