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.

Nitric oxide signaling in health and disease

“…Besides vasodilation, cGMP also mediates angiogenesis and neovascularization mainly through activation of HIF1a and VEGF signaling (Papapetropoulos et al, 1997), both of which may promote tumor growth and spread. In support of this, Schenk and colleagues recently demonstrated upregulation of sGC during progression of small cell lung cancer that correlated with acquired chemotherapy resistance in vivo (Schenk et al, 2021). At higher concentrations, for example, when generated by iNOS, NO or its reaction products can interact with nonheme-iron or critical thiols in proteins to modulate their activity and also directly interfere with cellular respiration through inhibition of cytochrome c oxidase (Sen et al, 2013) and nitrosation of complex 1 (Moncada, 2015), which in turn affects HIF1a-dependent pathways.…”

A Novel Small Molecular Inhibitor of DNMT1 Enhances the Antitumor Effect of Radiofrequency Ablation in Lung Squamous Cell Carcinoma Cells

“…The Notch pathway is an important regulator of tumor cell drug resistance ( Schenk et al, 2021 ; Zhang et al, 2022 ). There is increasing evidence to suggest that inhibition of the Notch pathway can upregulate the sensitivity of malignant tumor cells to radiotherapy and antitumor drugs ( Yang et al, 2021 ).…”

Identification of the effects of COVID-19 on patients with pulmonary fibrosis and lung cancer: a bioinformatics analysis and literature review

“…SCLC is an aggressive high-grade neuroendocrine malignancy and one of the deadliest solid tumors 123 . Among cancer patients, those with SCLC have one of the worst survival rates, with an overall 5-year survival rate of approximately 5% 124 , 125 . SCLC is characterized by a rapid doubling time and high growth fraction, and approximately two-thirds of patients present with metastases at the time of diagnosis 126 .…”