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Soluble guanylate cyclase signalling mediates etoposide resistance in progressing small cell lung cancer
Schenk, Maximilian W. Humphrey, Sam Hossain, AS Md Mukarram Revill, Mitchell Pearsall, Sarah Lallo, Alice Brown, Stewart Bratt, Samuel Galvin, Melanie Descamps, Tine
Schenk, Maximilian W.
Humphrey, Sam
Hossain, AS Md Mukarram
Revill, Mitchell
Pearsall, Sarah
Lallo, Alice
Brown, Stewart
Bratt, Samuel
Galvin, Melanie
Descamps, Tine
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Abstract
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.
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.
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.
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Date
2021
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Article
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.