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

Maximilian W Schenk; Sam Humphrey; A S Md Mukarram Hossain; Mitchell Revill; Sarah Pearsall; Alice Lallo; Stewart Brown; Samuel Bratt; Melanie Galvin; Tine Descamps; Cong Zhou; Simon P Pearce; Lynsey Priest; Michelle Greenhalgh; Anshuman Chaturvedi; Alastair Kerr; Fiona Blackhall; Caroline Dive; Kristopher K Frese

doi:10.1038/s41467-021-26823-6

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

Maximilian W Schenk, Sam Humphrey, A S Md Mukarram Hossain, Mitchell Revill, Sarah Pearsall, Alice Lallo, Stewart Brown, Samuel Bratt, Melanie Galvin, Tine Descamps, Cong Zhou, Simon P Pearce, Lynsey Priest, Michelle Greenhalgh, Anshuman Chaturvedi, Alastair Kerr, Fiona Blackhall, Caroline Dive, Kristopher K Frese

University of Manchester

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	6652
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-26823-6
Publication status	Published - 17 Nov 2021

Keywords

Animals
Cyclic GMP-Dependent Protein Kinases/metabolism
Disease Models, Animal
Disease Progression
Drug Resistance, Neoplasm/drug effects
Enzyme Inhibitors/therapeutic use
Etoposide/therapeutic use
Gene Expression Regulation, Neoplastic
Humans
Lung Neoplasms/drug therapy
Mice
Neoplastic Cells, Circulating/metabolism
Nitric Oxide/metabolism
Nitric Oxide Synthase Type II/antagonists & inhibitors
Receptors, Notch/metabolism
Signal Transduction/genetics
Small Cell Lung Carcinoma/drug therapy
Soluble Guanylyl Cyclase/genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-021-26823-6

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Schenk, M. W., Humphrey, S., Hossain, A. S. M. M., Revill, M., Pearsall, S., Lallo, A., Brown, S., Bratt, S., Galvin, M., Descamps, T., Zhou, C., Pearce, S. P., Priest, L., Greenhalgh, M., Chaturvedi, A., Kerr, A., Blackhall, F., Dive, C., & Frese, K. K. (2021). Soluble guanylate cyclase signalling mediates etoposide resistance in progressing small cell lung cancer. Nature Communications, 12(1), 6652. https://doi.org/10.1038/s41467-021-26823-6

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title = "Soluble guanylate cyclase signalling mediates etoposide resistance in progressing small cell lung cancer",

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.",

keywords = "Animals, Cyclic GMP-Dependent Protein Kinases/metabolism, Disease Models, Animal, Disease Progression, Drug Resistance, Neoplasm/drug effects, Enzyme Inhibitors/therapeutic use, Etoposide/therapeutic use, Gene Expression Regulation, Neoplastic, Humans, Lung Neoplasms/drug therapy, Mice, Neoplastic Cells, Circulating/metabolism, Nitric Oxide/metabolism, Nitric Oxide Synthase Type II/antagonists & inhibitors, Receptors, Notch/metabolism, Signal Transduction/genetics, Small Cell Lung Carcinoma/drug therapy, Soluble Guanylyl Cyclase/genetics",

author = "Schenk, {Maximilian W} and Sam Humphrey and Hossain, {A S Md Mukarram} and Mitchell Revill and Sarah Pearsall and Alice Lallo and Stewart Brown and Samuel Bratt and Melanie Galvin and Tine Descamps and Cong Zhou and Pearce, {Simon P} and Lynsey Priest and Michelle Greenhalgh and Anshuman Chaturvedi and Alastair Kerr and Fiona Blackhall and Caroline Dive and Frese, {Kristopher K}",

note = "{\textcopyright} 2021. The Author(s).",

year = "2021",

month = nov,

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doi = "10.1038/s41467-021-26823-6",

language = "English",

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journal = "Nature Communications",

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Schenk, MW, Humphrey, S, Hossain, ASMM, Revill, M, Pearsall, S, Lallo, A, Brown, S, Bratt, S, Galvin, M, Descamps, T, Zhou, C , Pearce, SP, Priest, L, Greenhalgh, M, Chaturvedi, A, Kerr, A, Blackhall, F, Dive, C & Frese, KK 2021, 'Soluble guanylate cyclase signalling mediates etoposide resistance in progressing small cell lung cancer', Nature Communications, vol. 12, no. 1, pp. 6652. https://doi.org/10.1038/s41467-021-26823-6

TY - JOUR

T1 - Soluble guanylate cyclase signalling mediates etoposide resistance in progressing small cell lung cancer

AU - Schenk, Maximilian W

AU - Humphrey, Sam

AU - Hossain, A S Md Mukarram

AU - Revill, Mitchell

AU - Pearsall, Sarah

AU - Lallo, Alice

AU - Brown, Stewart

AU - Bratt, Samuel

AU - Galvin, Melanie

AU - Descamps, Tine

AU - Zhou, Cong

AU - Pearce, Simon P

AU - Priest, Lynsey

AU - Greenhalgh, Michelle

AU - Chaturvedi, Anshuman

AU - Kerr, Alastair

AU - Blackhall, Fiona

AU - Dive, Caroline

AU - Frese, Kristopher K

PY - 2021/11/17

Y1 - 2021/11/17

N2 - 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.

AB - 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.

KW - Animals

KW - Cyclic GMP-Dependent Protein Kinases/metabolism

KW - Disease Models, Animal

KW - Disease Progression

KW - Drug Resistance, Neoplasm/drug effects

KW - Enzyme Inhibitors/therapeutic use

KW - Etoposide/therapeutic use

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Lung Neoplasms/drug therapy

KW - Mice

KW - Neoplastic Cells, Circulating/metabolism

KW - Nitric Oxide/metabolism

KW - Nitric Oxide Synthase Type II/antagonists & inhibitors

KW - Receptors, Notch/metabolism

KW - Signal Transduction/genetics

KW - Small Cell Lung Carcinoma/drug therapy

KW - Soluble Guanylyl Cyclase/genetics

U2 - 10.1038/s41467-021-26823-6

DO - 10.1038/s41467-021-26823-6

M3 - Article

C2 - 34789728

SN - 2041-1723

VL - 12

SP - 6652

JO - Nature Communications

JF - Nature Communications

IS - 1

ER -

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

Abstract

Keywords

UN SDGs

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