Soluble guanylate cyclase signalling mediates etoposide resistance in progressing small cell lung cancer.

Autor: Schenk MW; Cancer Research UK Manchester Institute Cancer Biomarker Centre, University of Manchester, Alderley Park, Macclesfield, SK10 4TG, UK., Humphrey S; Cancer Research UK Manchester Institute Cancer Biomarker Centre, University of Manchester, Alderley Park, Macclesfield, SK10 4TG, UK., Hossain ASMM; Cancer Research UK Manchester Institute Cancer Biomarker Centre, University of Manchester, Alderley Park, Macclesfield, SK10 4TG, UK., Revill M; Cancer Research UK Manchester Institute Cancer Biomarker Centre, University of Manchester, Alderley Park, Macclesfield, SK10 4TG, UK., Pearsall S; Cancer Research UK Manchester Institute Cancer Biomarker Centre, University of Manchester, Alderley Park, Macclesfield, SK10 4TG, UK., Lallo A; Cancer Research UK Manchester Institute Cancer Biomarker Centre, University of Manchester, Alderley Park, Macclesfield, SK10 4TG, UK., Brown S; Cancer Research UK Manchester Institute Cancer Biomarker Centre, University of Manchester, Alderley Park, Macclesfield, SK10 4TG, UK., Bratt S; Cancer Research UK Manchester Institute Cancer Biomarker Centre, University of Manchester, Alderley Park, Macclesfield, SK10 4TG, UK., Galvin M; Cancer Research UK Manchester Institute Cancer Biomarker Centre, University of Manchester, Alderley Park, Macclesfield, SK10 4TG, UK., Descamps T; Cancer Research UK Manchester Institute Cancer Biomarker Centre, University of Manchester, Alderley Park, Macclesfield, SK10 4TG, UK., Zhou C; Cancer Research UK Manchester Institute Cancer Biomarker Centre, University of Manchester, Alderley Park, Macclesfield, SK10 4TG, UK., Pearce SP; Cancer Research UK Manchester Institute Cancer Biomarker Centre, University of Manchester, Alderley Park, Macclesfield, SK10 4TG, UK., Priest L; Cancer Research UK Manchester Institute Cancer Biomarker Centre, University of Manchester, Alderley Park, Macclesfield, SK10 4TG, UK., Greenhalgh M; Christie National Health Service Foundation Trust, Division of Cancer Sciences, The University of Manchester, Manchester, M20 4BX, UK., Chaturvedi A; Christie National Health Service Foundation Trust, Division of Cancer Sciences, The University of Manchester, Manchester, M20 4BX, UK., Kerr A; Cancer Research UK Manchester Institute Cancer Biomarker Centre, University of Manchester, Alderley Park, Macclesfield, SK10 4TG, UK.; Cancer Research UK Lung Cancer Centre of Excellence at the University of Manchester, Oxford Road, Manchester, M13 9PL, UK., Blackhall F; Christie National Health Service Foundation Trust, Division of Cancer Sciences, The University of Manchester, Manchester, M20 4BX, UK.; Cancer Research UK Lung Cancer Centre of Excellence at the University of Manchester, Oxford Road, Manchester, M13 9PL, UK.; Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PL, UK., Dive C; Cancer Research UK Manchester Institute Cancer Biomarker Centre, University of Manchester, Alderley Park, Macclesfield, SK10 4TG, UK. caroline.dive@manchester.ac.uk.; Cancer Research UK Lung Cancer Centre of Excellence at the University of Manchester, Oxford Road, Manchester, M13 9PL, UK. caroline.dive@manchester.ac.uk., Frese KK; Cancer Research UK Manchester Institute Cancer Biomarker Centre, University of Manchester, Alderley Park, Macclesfield, SK10 4TG, UK.; Cancer Research UK Lung Cancer Centre of Excellence at the University of Manchester, Oxford Road, Manchester, M13 9PL, UK.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2021 Nov 17; Vol. 12 (1), pp. 6652. Date of Electronic Publication: 2021 Nov 17.
DOI: 10.1038/s41467-021-26823-6
Abstrakt: 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.
(© 2021. The Author(s).)
Databáze: MEDLINE
Externí odkaz: