Targeting Growth Hormone Receptor to Overcome Therapy Resistance in Non-Small Cell Lung Cancer

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.