Soluble guanylate cyclase signalling mediates etoposide resistance in progressing small cell lung cancer.
Maximilian W SchenkSam HumphreyA S Md Mukarram HossainMitchell RevillSarah PearsallAlice LalloStewart BrownSamuel BrattMelanie GalvinTine DescampsCong ZhouSimon P PearceLynsey PriestMichelle GreenhalghAnshuman ChaturvediAlastair R W KerrFiona BlackhallCaroline DiveKristopher K FresePublished in: Nature communications (2021)
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.
Keyphrases
- small cell lung cancer
- locally advanced
- nitric oxide
- protein kinase
- chemotherapy induced
- climate change
- single cell
- acute myeloid leukemia
- acute lymphoblastic leukemia
- cell proliferation
- brain metastases
- squamous cell carcinoma
- oxidative stress
- diffuse large b cell lymphoma
- genome wide
- radiation therapy
- hydrogen peroxide
- endoplasmic reticulum stress
- copy number
- signaling pathway
- drug delivery
- binding protein
- mesenchymal stem cells
- long non coding rna
- human health
- loop mediated isothermal amplification