ONC201 is a first-in-class small molecule inducer of the integrated stress response that is currently in phase II clinical trials in select advanced cancers with promising early clinical results. The efficacy of this novel agent has been demonstrated in numerous preclinical advance cancer models in multiple indications with an exceptional safety profile that has translated well to the clinic. To determine the preclinical sensitivity profile of ONC201 in cancer, we performed an in vitro efficacy screen across >1,000 human cancer cell lines that represent a diverse array of tumor types and genetic aberrations. Sensitivity profiling was assessed by cell viability assays using dose responses curves at concentrations up to 20uM and at 72 hours post-treatment. Ranking the sensitivity dataset by tumor type, non-Hodgkin's lymphomas and multiple myeloma were the most sensitive tumor type to ONC201.

The mutation-agnostic efficacy that is most pronounced in lymphomas and multiple myeloma is in accordance with the recent findings that ONC201 induces the integrated stress response through a novel target to trigger is downstream late apoptotic effects. B-cell malignancies are particularly susceptible to induction of apoptosis via the integrated stress response, as they have relatively high basal activation of this pathway due to ER stress conferred by immunoglobulin production. Confirmatory studies revealed that multiple myeloma cell lines indeed possess pronounced sensitivity with nanomolar GI50s, unlike most other tumor types, that is particularly encouraging given the systemic concentrations observed in the first-in-man study. Together, these studies suggest specific advanced cancer indications, such as non-Hodgkin's lymphoma and multiple myeloma, as promising lead indications for this novel agent that are being evaluated in phase II clinical trials.


Allen:Oncoceutics, Inc: Employment, Equity Ownership. Tarapore:Oncoceutics, Inc: Employment, Equity Ownership.

Author notes


Asterisk with author names denotes non-ASH members.