APR-246 (
Eprenetapopt/PRIMA-1Met) is a very potent anti-
cancer drug in clinical trials and was initially developed as a p53 refolding agent. As an alternative mode of action, the elevation of
reactive oxygen species (ROS) has been proposed. Through an in silico analysis, we investigated the responses of approximately 800
cancer cell lines (50 entities;
Cancer Therapeutics Response Portal, CTRP) to
APR-246 treatment. In particular,
neuroblastoma,
lymphoma and
acute lymphocytic leukemia cells were highly responsive. With gene expression data from the
Cancer Cell Line Encyclopedia (CCLE; n = 883) and patient samples (n = 1643) from the INFORM registry study, we confirmed that these entities express low levels of SLC7A11, a previously described predictive
biomarker for
APR-246 responsiveness. Combining the CTRP drug response data with the respective CCLE gene expression profiles, we defined a novel gene signature, predicting the effectiveness of
APR-246 treatment with a sensitivity of 90% and a specificity of 94%. We confirmed the predicted
APR-246 sensitivity in 8/10 cell lines and in ex vivo cultures of patient samples. Moreover, the combination of ROS detoxification-impeding
APR-246 with approved
HDAC-inhibitors, known to elevate ROS, substantially increased
APR-246 sensitivity in cell cultures and in vivo in two zebrafish
neuroblastoma xenograft models. These data provide evidence that
APR-246, in combination with
HDAC-inhibitors, displays a novel potent targeted treatment option for
neuroblastoma patients.