Abstract 386: High CRBN expression in neuroendocrine cancer creates a vulnerability to GSPT1 molecular glue degraders: Target indication selection for CYRS1542 development

Abstract Multiple companies have been developing GSPT1-targeted molecular glue degraders (MGDs) for neuroendocrine (NE) cancers, a rare and aggressive cancer type. CYRS1542, a potent and orally bioavailable GSPT1 MGD with a superior therapeutic index, was identified and derived from CYRS381 (originally known as SJ6986) in our previous work (Joo et al., AACR 2024). In this study, we investigated the mechanistic basis of GSPT1 MGD sensitivity in NE cancers, using CYRS381 as a tool compound to assess selective susceptibilities. We found that CYRS381-induced GSPT1 degradation was selectively effective in the NE cancers with high CRBN expression, while the non-NE cancers with a low level of CRBN showed limited response. NE cancer cells positive for NE markers exhibited both higher CRBN expression and greater sensitivity to CYRS381, showing rapid GSPT1 degradation upon GSPT1 MGD treatment compared to non-NE cancer cells. Further analysis of TCGA and DepMap expression data revealed a significant positive correlation between high CRBN levels and NE characteristics, whereas GSPT1 levels showed no such correlation. Consistently, overexpressing CRBN in non-NE cancer cells increased sensitivity to GSPT1 MGD, and introducing NE-driving factors in non-NE cancer cells elevated CRBN expression, further enhancing the response to GSPT1 MGD. Finally, CYRS1542 demonstrated effects similar to CYRS381 in comparable experiments, further supporting the selection of NE cancers as the lead indication for its clinical trials. Overall, these findings highlight CRBN as a key determinant of GSPT1 MGD efficacy and underscore the potential of CYRS1542 as a targeted therapeutic option for aggressive NE cancers. Citation Format: Jaewoo Park, Min Sung Joo, JaeYung Lee, Eun-Jung Kim, Dong Hyuk Ki, Hunmi Choi, Wooseok Han, Keon Wook Kang. High CRBN expression in neuroendocrine cancer creates a vulnerability to GSPT1 molecular glue degraders: Target indication selection for CYRS1542 development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 386.