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Targeting Growth Hormone Receptor to Overcome Therapy Resistance in Non-Small Cell Lung Cancer
Arshad Ahmad1,2,3, Reetobrata Basu1, Caden Fyffe1,4
1Institute for Molecular Medicine and Aging and Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA.
Abstract:
Lung cancer (LC) remains the leading cause of cancer-related death in the United States despite advances in therapy. Growth hormone (GH) action has been implicated in tumor progression and therapy resistance across multiple cancers, but its role in LC, particularly non-small cell lung cancer (NSCLC), remains poorly defined. In cancer cells, GH promotes chemoresistance through upregulation of drug-efflux pumps, induction of epithelial-to-mesenchymal transition (EMT), and inhibition of apoptosis. Notably, GH receptor (GHR) expression is significantly elevated in NSCLC compared to normal lung tissue, suggesting a potential therapeutic opportunity. In this study, we investigated the impact of GH action on therapy resistance and tumor progression using integrated transcriptomic analyses and in vitro experiments. Analyses of transcriptomic data from NSCLC patients revealed that high tumoral GHR expression correlates with reduced overall survival, and with upregulation of genes involved in distinct therapy refractory pathways. Our in vitro studies demonstrated that GH promotes chemoresistance in NSCLC cell lines through activation of ABC transporters and EMT pathways, whereas GHR antagonism with the GH receptor antagonist, pegvisomant, effectively counteracts these effects and improves chemotherapy efficacy significantly. Together, our findings identify GHR signaling as a contributor to aggressive and therapy-resistant phenotypes in NSCLC in vitro and suggest that GHR antagonism may enhance chemotherapy sensitivity. These results provide a rationale for further in vivo and mechanistic studies to evaluate the therapeutic potential of targeting GHR in NSCLC.
Insights
Growth hormone (GH) signaling drives non-small cell lung cancer (NSCLC) therapy resistance by activating drug efflux and epithelial-to-mesenchymal transition (EMT). Targeting the GH receptor (GHR) with antagonists enhances chemotherapy efficacy in NSCLC models.
Area of Science:
- Oncology
- Endocrinology
- Molecular Biology
Background:
- Lung cancer (LC) is a leading cause of cancer death, with non-small cell lung cancer (NSCLC) being the most common subtype.
- Growth hormone (GH) signaling is implicated in tumor progression and therapy resistance in various cancers.
- GH receptor (GHR) expression is elevated in NSCLC, suggesting a potential role in disease aggressiveness and treatment outcomes.
Purpose of the Study:
- To investigate the impact of GH signaling on therapy resistance and tumor progression in NSCLC.
- To explore the correlation between GHR expression and patient survival and therapy refractory pathways.
- To evaluate the efficacy of GHR antagonism in overcoming chemoresistance in NSCLC.
Main Methods:
- Integrated transcriptomic analyses of NSCLC patient data.
- In vitro experiments using NSCLC cell lines treated with GH and GHR antagonists.
- Assessment of gene expression related to drug-efflux pumps (ABC transporters) and epithelial-to-mesenchymal transition (EMT).
Main Results:
- High tumoral GHR expression in NSCLC patients correlates with reduced overall survival and upregulation of therapy-refractory genes.
- GH treatment promotes chemoresistance in NSCLC cell lines by activating ABC transporters and EMT pathways.
- GHR antagonism with pegvisomant counteracted GH-induced chemoresistance and significantly improved chemotherapy efficacy in vitro.
Conclusions:
- GH signaling contributes to aggressive and therapy-resistant phenotypes in NSCLC.
- GHR antagonism represents a potential therapeutic strategy to enhance chemotherapy sensitivity in NSCLC.
- Targeting GHR warrants further investigation in preclinical and clinical settings for NSCLC treatment.
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