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

Nat Commun. 2021 Nov 17;12(1):6652. doi: 10.1038/s41467-021-26823-6.

Authors

Maximilian W Schenk¹, Sam Humphrey¹, A S Md Mukarram Hossain¹, Mitchell Revill¹, Sarah Pearsall¹, Alice Lallo¹, Stewart Brown¹, Samuel Bratt¹, Melanie Galvin¹, Tine Descamps¹, Cong Zhou¹, Simon P Pearce¹, Lynsey Priest¹, Michelle Greenhalgh², Anshuman Chaturvedi², Alastair Kerr^{1

3}, Fiona Blackhall^{2

3

4}, Caroline Dive^{5

6}, Kristopher K Frese^{1

3}

Affiliations

¹ Cancer Research UK Manchester Institute Cancer Biomarker Centre, University of Manchester, Alderley Park, Macclesfield, SK10 4TG, UK.
² Christie National Health Service Foundation Trust, Division of Cancer Sciences, The University of Manchester, Manchester, M20 4BX, UK.
³ Cancer Research UK Lung Cancer Centre of Excellence at the University of Manchester, Oxford Road, Manchester, M13 9PL, UK.
⁴ Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PL, UK.
⁵ Cancer Research UK Manchester Institute Cancer Biomarker Centre, University of Manchester, Alderley Park, Macclesfield, SK10 4TG, UK. [email protected].
⁶ Cancer Research UK Lung Cancer Centre of Excellence at the University of Manchester, Oxford Road, Manchester, M13 9PL, UK. [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cyclic GMP-Dependent Protein Kinases / metabolism
Disease Models, Animal
Disease Progression
Drug Resistance, Neoplasm / drug effects*
Drug Resistance, Neoplasm / genetics
Enzyme Inhibitors / therapeutic use
Etoposide / therapeutic use*
Gene Expression Regulation, Neoplastic
Humans
Lung Neoplasms / drug therapy
Lung Neoplasms / genetics
Lung Neoplasms / metabolism*
Lung Neoplasms / pathology
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
Small Cell Lung Carcinoma / metabolism*
Small Cell Lung Carcinoma / pathology
Soluble Guanylyl Cyclase / genetics
Soluble Guanylyl Cyclase / metabolism*

Substances

Enzyme Inhibitors
Receptors, Notch
Nitric Oxide
Etoposide
Nitric Oxide Synthase Type II
Cyclic GMP-Dependent Protein Kinases
Soluble Guanylyl Cyclase

Abstract

Publication types

MeSH terms

Substances

Grants and funding