Small cell lung cancer and prostate cancer cells with varying neuroendocrine differentiation markers show sensitivity to imipridone ONC201/TIC10.

Abstract

Objectives: To investigate whether neuroendocrine differentiation (NED) markers, activation of the integrated stress response (ISR), and TRAIL pathway alter neuroendocrine tumor (NET) cell death and ONC201 sensitivity.

Methods: We conducted cell viability assays to determine ONC201 sensitivity. Western blot analysis was performed to evaluate NED, ISR, and TRAIL pathway markers. Expression levels of NED markers were compared between cell lines with and without BRN2 overexpression.

Results: Prostate cancer (PCa) and small cell lung cancer (SCLC) cell lines (N = 6) were sensitive to ONC201. Endogenous NET marker levels varied across PCa and SCLC cells. Transient BRN2 overexpression slightly reduced some NET markers while maintaining the sensitivity of PCa cells to ONC201.

Conclusions: PCa cell lines exhibit sensitivity to ONC201, with variability of NED features. These findings are relevant to the design of future studies evaluating imipridone efficacy in PCa and suggest that non-NET patients could be included in such studies.