In a groundbreaking study that may redefine therapeutic approaches in oncology, scientists at Ohio University have unveiled a potential strategy to combat resistance in Non-Small Cell Lung Cancer (NSCLC), one of the deadliest and most common forms of lung cancer worldwide. The research, published recently in the International Journal of Molecular Sciences, investigates the role of growth hormone receptor (GHR) signaling in the development and progression of therapy-resistant lung tumors, providing new insight into the disease’s molecular underpinnings.
Lung cancer persists as the leading cause of cancer mortality globally, with NSCLC accounting for approximately 80 to 85 percent of all lung cancer cases. Despite continuous advancements in conventional treatments such as surgery, chemotherapy, radiation, and targeted therapy, many patients ultimately develop resistance, significantly diminishing the efficacy of these interventions and adversely affecting survival outcomes. Finding novel targets to reverse or circumvent this resistance is thus a critical priority in current cancer research.
Central to this study was the examination of the growth hormone (GH) pathway, traditionally known for its regulatory roles in growth, metabolism, and development. GH exerts its biological effects by binding to the growth hormone receptor (GHR), a transmembrane protein that activates intracellular signaling cascades upon ligand engagement. Emerging evidence suggests aberrant expression and activation of GH and GHR can contribute to oncogenesis and tumor progression, but their impact on lung cancer, particularly in the context of drug resistance, has been inadequately understood.
Employing comprehensive bioinformatic analyses on extensive patient datasets, including genomic and transcriptomic data from The Cancer Genome Atlas (TCGA), the research team compared GHR expression levels in tumor samples relative to normal lung tissue. The results revealed a pronounced overexpression of GHR in NSCLC tumors, highlighting a potential oncogenic role of GH signaling in lung carcinogenesis. This overexpression was not merely a biomarker but correlated directly with clinical outcomes.
The survival analysis conducted as part of the study was particularly striking: patients with tumors exhibiting high GHR expression had markedly shorter overall survival, with median survival times plummeting to between 36 and 40 months. In contrast, those with tumors expressing low levels of GHR had a median survival of roughly 66 months. This stark difference underscores a robust prognostic significance of GHR and signals its potential as a therapeutic target.
In vitro experiments further elucidated the mechanisms behind GH-induced therapy resistance. When human and mouse lung cancer cells were exposed to growth hormone, they demonstrated increased resistance to chemotherapy agents such as doxorubicin and cisplatin, drugs commonly employed in lung cancer treatment protocols. This resistance was mechanistically linked to enhanced activity of drug-efflux pumps—protein complexes that actively transport chemotherapeutic compounds out of cancer cells, thereby reducing intracellular drug concentrations and efficacy.
Moreover, GH exposure induced cellular changes associated with enhanced metastatic potential and reduced apoptosis. These alterations included modifications in signaling pathways that regulate epithelial-mesenchymal transition and cell survival. Collectively, these findings illustrate how GH signaling confers a more aggressive phenotype to lung cancer cells that not only withstand chemotherapeutic assault but also exhibit increased capacity for tumor spread.
To explore therapeutic avenues, the study investigated the efficacy of pegvisomant, a GH receptor antagonist approved by the FDA for the treatment of acromegaly, a disorder characterized by excessive GH production. Pegvisomant binds to GHR, blocking its activation and subsequent downstream signaling. Notably, the drug was discovered by John J. Kopchick, the lead investigator, decades ago, highlighting a scientific journey bridging fundamental discovery and clinical application.
Laboratory assays demonstrated that pegvisomant effectively counteracted the pro-survival and drug-resistant effects induced by GH in lung cancer cells. Importantly, when pegvisomant was combined with chemotherapy, cancer cells exhibited heightened sensitivity to the drugs, allowing effective tumor cell killing at lower chemotherapeutic doses. This potentiation suggests that GHR blockade may synergistically enhance existing treatment regimens while potentially mitigating chemotherapy-associated toxicity.
Despite the promising laboratory results and compelling correlation with clinical data, the study emphasizes the current limitations and requisite next steps. All findings to date are derived from computational analysis of patient data and experiments in cultured cell lines; in vivo validation remains essential. Encouragingly, prior animal studies conducted by the team and collaborators demonstrated significant therapeutic benefits of combining pegvisomant with standard therapies in mouse models of melanoma, pancreatic, and liver cancers. The forthcoming phase involves applying these approaches to NSCLC mouse models to evaluate efficacy and safety profiles in a complex biological system.
If preclinical studies yield positive results, they will pave the way for clinical trials designed to assess whether targeting GHR can safely and effectively overcome drug resistance in lung cancer patients. Such trials will be critical to ascertain the translational potential and clinical utility of this novel therapeutic strategy.
The study represents a collaborative effort among Ohio University’s Institute for Molecular Medicine and the Aging, the Diabetes Institute, the Translational Biomedical Sciences Program, and departmental divisions of Biomedical and Biological Sciences. International cooperation was also integral, incorporating expertise from Erasmus Medical Centre in the Netherlands, underscoring the global commitment to overcoming the challenges posed by lung cancer.
This innovative research advances our understanding of growth hormone’s paradoxical role in cancer biology and opens new investigative pathways in the quest to enhance pulmonary oncology outcomes. The evidence positions GHR not only as a biomarker of poor prognosis but as a modifiable target that could revolutionize lung cancer treatment by overcoming one of its greatest obstacles: therapy resistance.
Subject of Research: Cells
Article Title: Targeting Growth Hormone Receptor to Overcome Therapy Resistance in Non-Small Cell Lung Cancer
News Publication Date: 22-Dec-2025
Web References: https://www.mdpi.com/1422-0067/27/1/115
Keywords: Growth hormone, Lung cancer, Cells, Cancer cells, Drug interactions, Drug studies, Drug resistance
