SAT-290 Growth Hormone Receptor Antagonism Markedly Improves Chemotherapy Efficacy Against Human Lung Cancer

Abstract Disclosure: A. Ahmad: None. R. Basu: None. J.J. Kopchick: None. Despite the improvement in therapies, lung cancer (LC) persists as the leading cause of cancer death in the United States. We and others have identified and described that human growth hormone (GH) promotes chemoresistance in tumor cells via upregulation of drug-efflux pumps, upregulation of molecular markers of metastasis, and inhibition of apoptosis. GH receptor (GHR) antagonism can reverse these effects and improve antineoplastic efficacy in liver, breast, endometrium, colon, pancreas, bile duct, and melanoma cancers. Mounting evidence corroborates a close association of GH action in LC, yet none have studied GH action in driving chemoresistance or the benefits of GHR antagonism to improve chemotherapeutic outcomes in LC. Compared to normal lung tissue, GHR is significantly overexpressed in the microenvironment of non-small cell LC (NSCLC). Together, these facts provide a provocative rationale to inquire if a GHR antagonist, Pegvisomant, can improve therapeutic outcomes in NSCLC, which affects millions of patients annually. Here we present an analysis of the role of GH action in the highly therapy-resistant human NSCLC, which has a 5-year survival rate of 28%. Therefore, I hypothesize that GHR antagonism can attenuate mechanisms of therapy resistance and markedly improve the efficacy of anti-cancer therapies against NSCLC. We validated our hypothesis in human (H1299, H1703) and mouse (LLC1) NSCLC cells using RT-qPCR and western blot analysis. We identified that GH upregulates the expression of specific ATP-binding cassette (ABC) transporters and epithelial-to-mesenchymal transition (EMT) transcription factors in human and mouse NSCLC. Pegvisomant significantly inhibited these effects. We further verified our results by using The Cancer Genome Atlas from patients with NSCLC. Interestingly, a decrease in overall survival was observed in patients whose tumors express high levels of GHR in comparison to patients whose tumors express low levels of GHR. Correlation analyses of differentially expressed mRNAs with respect to GHR expression in tumor samples were performed, which confirmed that LC patients with high GHR expression were positively correlated with molecular markers of therapy resistance and metastasis. Additionally, by using a viability assay, we confirmed an increase in IC50 of doxorubicin and cisplatin in LC cells treated with GH and a decrease in IC50 treated with Pegvisomant. Moreover, by using an invasion assay, we confirmed that GH increases basement membrane invasion, while Pegvisomant reverses the invasion in human and mouse NSCLC cells. Presently, we are validating our observation in a mouse model of LC. In conclusion, our in vitro results confirm that GHR antagonism can drastically sensitize human and mouse LC cells by blocking mechanisms of drug resistance and EMT, thus providing a valuable window for improved efficacy of available anticancer therapies. Presentation: Saturday, July 12, 2025