Soluble guanylate cyclase signalling mediates etoposide resistance in progressing small cell lung cancer
AuthorsSchenk, Maximilian W.
Hossain, A. S. Md Mukarram
Pearce, Simon P.; orcid: 0000-0002-1680-5538
Kerr, Alastair; orcid: 0000-0001-9207-6050
Dive, Caroline; orcid: 0000-0002-1726-8850; email: email@example.com
Frese, Kristopher K.; orcid: 0000-0002-1369-0907
MetadataShow full item record
AbstractAbstract: Small cell lung cancer (SCLC) has a 5-year survival rate of <7%. Rapid emergence of acquired resistance to standard platinum-etoposide chemotherapy is common and improved therapies are required for this recalcitrant tumour. We exploit six paired pre-treatment and post-chemotherapy circulating tumour cell patient-derived explant (CDX) models from donors with extensive stage SCLC to investigate changes at disease progression after chemotherapy. Soluble guanylate cyclase (sGC) is recurrently upregulated in post-chemotherapy progression CDX models, which correlates with acquired chemoresistance. Expression and activation of sGC is regulated by Notch and nitric oxide (NO) signalling with downstream activation of protein kinase G. Genetic targeting of sGC or pharmacological inhibition of NO synthase re-sensitizes a chemoresistant CDX progression model in vivo, revealing this pathway as a mediator of chemoresistance and potential vulnerability of relapsed SCLC.
CitationNature Communications, volume 12, issue 1, page 6652
PublisherNature Publishing Group UK
DescriptionFrom Springer Nature via Jisc Publications Router
History: received 2020-12-10, accepted 2021-10-19, registration 2021-10-26, pub-electronic 2021-11-17, online 2021-11-17, collection 2021-12
Publication status: Published
Funder: CRUK Manchester Institute (grant no. A27412) CRUK Manchester Centre (grant no. A25254) CRUK Manchester Experimental Cancer Medicines Centre (grant no. A20465) CRUK Lung Cancer Centre of Excellence (grant no. A25146) NIHR Manchester Biomedical Research Centre