Therapeutic targeting RORγ with natural product N-hydroxyapiosporamide for small cell lung cancer by reprogramming neuroendocrine fate

Small cell lung cancer (SCLC) is an aggressive and exceptionally fatal disease. Unlike non- small cell lung cancer (NSCLC), no targetable genetic driver events have been identified in SCLC to date. Here, we investigate the function of RAR-related orphan receptor gamma (ROR gamma) and identified the anti-cancer activity of its natural inhibitor against SCLC and illustrate the underlying mechanism. We show that ROR gamma depletion affected cell growth both in 2-D cell proliferation and 3-D organoids formation. Natural marine product N-hydroxyapiosporamide (N-hydap) directly bound to ROR gamma and inhibited its transcriptional activity, leading to the blocking of transmission process of ROR gamma signaling. Gene expression profiling analysis revealed that N-hydap reprograms neuroendocrine fate via inhibiting ROR gamma activity in SCLC. Chromatin immunoprecipitation analysis showed that N-hydap strongly reduced ROR gamma occupancy and transcriptional activation-linked histone marks H3K27ac on the promoter and/or enhancer sites of neurogenesis markers gene including aurora kinase a (AURKA), delta like canonical Notch ligand 3 (DLL3) and tubulin beta 3 class III (TUBB3). Therapeutically, Nhydap exhibited a strong inhibitory effect on tumor growth and did not show significant toxicity in SCLC mice xenograft models. Taken together, ROR gamma could be an attractive target for SCLC and thus N-hydap can be a promising therapeutic drug candidate for SCLC by inhibiting the ROR gamma activation.

Automated summary

This study reveals the function of RAR-related orphan receptor gamma (RORγ) in small cell lung cancer (SCLC) and identifies the anti-cancer activity of its natural inhibitor, N-hydroxyapiosporamide (N-hydap). The findings show that depletion of RORγ affects cell growth in SCLC and N-hydap inhibits RORγ activity, leading to reprogramming of neuroendocrine fate. The study suggests that RORγ could be a potential target for SCLC and N-hydap may be a promising therapeutic drug candidate.