Protein neddylation as a therapeutic target in pulmonary and extrapulmonary small cell carcinomas
Justin P Norton1,2, Arnaud Augert1,2, Emily Eastwood1,2
1Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Abstract:
Small cell lung carcinoma (SCLC) is among the most lethal of all solid tumor malignancies. In an effort to identify novel therapeutic approaches for this recalcitrant cancer type, we applied genome-scale CRISPR/Cas9 inactivation screens to cell lines that we derived from a murine model of SCLC. SCLC cells were particularly sensitive to the deletion of NEDD8 and other neddylation pathway genes. Genetic suppression or pharmacological inhibition of this pathway using MLN4924 caused cell death not only in mouse SCLC cell lines but also in patient-derived xenograft (PDX) models of pulmonary and extrapulmonary small cell carcinoma treated ex vivo or in vivo. A subset of PDX models were exceptionally sensitive to neddylation inhibition. Neddylation inhibition suppressed expression of major regulators of neuroendocrine cell state such as INSM1 and ASCL1, which a subset of SCLC rely upon for cell proliferation and survival. To identify potential mechanisms of resistance to neddylation inhibition, we performed a genome-scale CRISPR/Cas9 suppressor screen. Deletion of components of the COP9 signalosome strongly mitigated the effects of neddylation inhibition in small cell carcinoma, including the ability of MLN4924 to suppress neuroendocrine transcriptional program expression. This work identifies neddylation as a regulator of neuroendocrine cell state and potential therapeutic target for small cell carcinomas.
Insights
Researchers identified neddylation as a crucial pathway in small cell lung carcinoma (SCLC). Inhibiting this pathway, particularly with MLN4924, shows promise in treating this aggressive cancer by targeting neuroendocrine cell state regulators.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Small cell lung carcinoma (SCLC) is a highly aggressive malignancy with limited therapeutic options.
- Novel therapeutic targets are urgently needed for recalcitrant SCLC.
Purpose of the Study:
- To identify novel therapeutic targets for SCLC using genome-scale CRISPR/Cas9 screens.
- To investigate the role of the neddylation pathway in SCLC pathogenesis and identify potential vulnerabilities.
Main Methods:
- Genome-scale CRISPR/Cas9 inactivation and suppressor screens were performed on murine SCLC cell lines.
- Pharmacological inhibition of neddylation using MLN4924 was tested in SCLC cell lines and patient-derived xenograft (PDX) models.
- Expression of neuroendocrine cell state regulators (INSM1, ASCL1) was analyzed following neddylation inhibition.
Main Results:
- SCLC cells exhibited sensitivity to the deletion of NEDD8 and other neddylation pathway genes.
- Neddylation inhibition with MLN4924 induced cell death in SCLC models and suppressed key neuroendocrine transcription factors.
- Components of the COP9 signalosome conferred resistance to neddylation inhibition.
Conclusions:
- Neddylation is a critical regulator of the neuroendocrine cell state in SCLC.
- Neddylation inhibition represents a promising therapeutic strategy for small cell carcinomas.
- Understanding resistance mechanisms involving the COP9 signalosome is important for optimizing neddylation-targeted therapies.
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