Soluble guanylate cyclase signalling mediates etoposide resistance in progressing small cell lung cancer
Authors
Schenk, Maximilian W.Humphrey, Sam
Hossain, AS Md Mukarram
Revill, Mitchell
Pearsall, Sarah
Lallo, Alice
Brown, Stewart
Bratt, Samuel
Galvin, Melanie
Descamps, Tine
Zhou, Cong
Pearce, Simon P
Priest, Lynsey
Greenhalgh, Michelle
Chaturvedi, Anshuman
Kerr, Alastair
Blackhall, Fiona H
Dive, Caroline
Frese, Kristopher K.
Affiliation
Cancer Research UK Manchester Institute Cancer Biomarker Centre, University of Manchester, Alderley Park, Macclesfield, SK10 4TG,Issue Date
2021
Metadata
Show full item recordAbstract
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.Citation
Schenk MW, Humphrey S, Hossain ASMM, Revill M, Pearsall S, Lallo A, et al. Soluble guanylate cyclase signalling mediates etoposide resistance in progressing small cell lung cancer Vol. 12, Nature Communications. Springer Science and Business Media LLC; 2021.Journal
Nature CommunicationsDOI
10.1038/s41467-021-26823-6PubMed ID
34789728Type
Articleae974a485f413a2113503eed53cd6c53
10.1038/s41467-021-26823-6
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