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

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.