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

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.

Ex vivo culture of cells derived from circulating tumour cell xenograft to support small cell lung cancer research and experimental therapeutics.

BACKGROUND AND PURPOSE: Small cell lung cancer (SCLC) is an aggressive disease with median survival of <2 years. Tumour biopsies for research are scarce, especially from extensive-stage patients, with repeat sampling at disease progression rarely performed. We overcame this limitation for relevant preclinical models by developing SCLC circulating tumour cell derived explants (CDX), which mimic the donor tumour pathology and chemotherapy response. To facilitate compound screening and identification of clinically relevant biomarkers, we developed short-term ex vivo cultures of CDX tumour cells. EXPERIMENTAL APPROACH: CDX tumours were disaggregated, and the human tumour cells derived were cultured for a maximum of 5 weeks. Phenotypic, transcriptomic and pharmacological characterization of these cells was performed. KEY RESULTS: CDX cultures maintained a neuroendocrine phenotype, and most changes in the expression of protein-coding genes observed in cultures, for up to 4 weeks, were reversible when the cells were re-implanted in vivo. Moreover, the CDX cultures exhibited a similar sensitivity to chemotherapy compared to the corresponding CDX tumour in vivo and were able to predict in vivo responses to therapeutic candidates. CONCLUSIONS AND IMPLICATIONS: Short-term cultures of CDX provide a tractable platform to screen new treatments, identify predictive and pharmacodynamic biomarkers and investigate mechanisms of resistance to better understand the progression of this recalcitrant tumour.

Circulating tumor cells and CDX models as a tool for preclinical drug development.

Lung cancers are the main cause of cancer-related deaths worldwide. Efforts placed to improve the survival of lung cancer patients and untangle the complexity of this disease, have resulted in the generation of hundreds of lung cancer cell lines and several genetically engineered mouse models (GEMMs). Although these research tools have extended our knowledge of lung cancer, improvement in the clinical care of lung cancer patients have been limited overall, with measured optimism regarding initial responses to targeted therapies in stratified subgroups of patients. Patient-derived xenograft (PDX) models are beginning to assist 'personalized therapy' approaches particularly in non-small cell lung cancer (NSCLC) however biopsies of lung cancers to generate PDXs are not without challenges and risks to the patient. Liquid biopsies, on the other hand, are a rapid and non-invasive procedure allowing the collection of circulating tumor cells (CTCs) with a single 10 mL blood draw. These CTCs recapitulate the molecular heterogeneity of the corresponding tumors and, therefore, can be used as surrogates to study tumor biology and generate new patient-derived models. Here, we discuss the CTC-derived models that have been generated, most notably in small cell lung cancer (SCLC), highlighting challenges and opportunities related to these novel preclinical tools.

Targeting DNA damage in SCLC.

SCLC accounts for 15% of lung cancer worldwide. Characterised by early dissemination and rapid development of chemo-resistant disease, less than 5% of patients survive 5 years. Despite 3 decades of clinical trials there has been no change to the standard platinum and etoposide regimen for first line treatment developed in the 1970's. The exceptionally high number of genomic aberrations observed in SCLC combined with the characteristic rapid cellular proliferation results in accumulation of DNA damage and genomic instability. To flourish in this precarious genomic context, SCLC cells are reliant on functional DNA damage repair pathways and cell cycle checkpoints. Current cytotoxic drugs and radiotherapy treatments for SCLC have long been known to act by induction of DNA damage and the response of cancer cells to such damage determines treatment efficacy. Recent years have witnessed improved understanding of strategies to exploit DNA damage and repair mechanisms in order to increase treatment efficacy. This review will summarise the rationale to target DNA damage response in SCLC, the progress made in evaluating novel DDR inhibitors and highlight various ongoing challenges for their clinical development in this disease.