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High cereblon expression in neuroendocrine cancer confers vulnerability to GSPT1 molecular glue degrader
Jaewoo Park1, Min Sung Joo2, Myung Jun Kim1
1College of Pharmacy, Research Institute of Pharmaceutical Sciences and Natural Product Research Institute, Seoul National University, Seoul, South Korea.
Background:
Recent advances in targeted therapies have introduced molecular glue degraders (MGDs) that leverage the cereblon (CRBN) E3 ubiquitin ligase to degrade the translation termination factor GSPT1. Understanding the cellular context for the selective targeting of cancer cells by GSPT1 MGDs is crucial.
Methods:
This study investigated the sensitivity of neuroendocrine cancer (NEC) cells to GSPT1MGDs across a pan-cancer cell line panel, examining the correlation between therapeutic response and cellular characteristics such as CRBN expression and neuroendocrine (NE) marker levels. The role of CRBN in enhancing MGD sensitivity was further validated through CRBN overexpression and NEC-driving factor expression experiments in non-NEC and lung adenocarcinoma cells. The sensitivity of acute myeloid leukemia (AML) cells, which share transcriptomic features with NECs, to GSPT1 MGDs was also evaluated.
Results:
NEC cells with high CRBN expression exhibited marked sensitivity to GSPT1 MGDs compared to other cancer types. GSPT1 degradation was more rapid and robust in NEC cells, highlighting the cellular context dependency of the treatment. A strong correlation was observed between CRBN expression and NE characteristics, whereas no such correlation was found with GSPT1 expression. CRBN overexpression in non-NEC cells significantly increased their sensitivity to GSPT1 MGDs, as did the ectopic expression of NEC-driving factors, which upregulated CRBN levels in lung adenocarcinoma cells. Additionally, AML cells, with high CRBN expression, showed similar sensitivity to GSPT1 MGDs, mirroring the behavior of NECs.
Conclusions:
CRBN expression is a critical determinant of the selective cytotoxicity of GSPT1 MGDs in NECs and other cancers with shared transcriptomic features, such as AML. These findings underscore the therapeutic potential of targeting NECs using GSPT1 MGDs, paving the way for a more refined and selective approach in treating aggressive cancers.
Insights
Cereblon (CRBN) expression dictates the effectiveness of GSPT1 molecular glue degraders (MGDs) against neuroendocrine cancers (NECs). High CRBN levels enhance GSPT1 MGD sensitivity in NECs and acute myeloid leukemia (AML), enabling targeted cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Molecular glue degraders (MGDs) targeting GSPT1 show promise in cancer therapy.
- Understanding the cellular context for MGD selectivity is crucial for effective cancer treatment.
Purpose of the Study:
- To investigate the sensitivity of neuroendocrine cancer (NEC) cells to GSPT1 MGDs.
- To determine the correlation between therapeutic response and cellular characteristics like CRBN expression.
Main Methods:
- Pan-cancer cell line analysis of GSPT1 MGD sensitivity.
- CRBN and neuroendocrine marker level assessment.
- CRBN and NEC-driving factor overexpression experiments.
Main Results:
- NEC cells with high CRBN expression were highly sensitive to GSPT1 MGDs.
- CRBN overexpression increased MGD sensitivity in non-NEC cells.
- Acute myeloid leukemia (AML) cells with high CRBN also showed sensitivity.
Conclusions:
- CRBN expression is a key factor for GSPT1 MGDs' selective toxicity in NECs and AML.
- GSPT1 MGDs hold therapeutic potential for aggressive cancers like NECs.
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