SUN-336 Autocrine / Paracrine Growth Hormone (GH) Drives Multimodal Therapy Resistance in Growth Hormone Receptor (GHR)-expressing Human Cancers

Abstract

Data from cell culture, mice, and human epidemiological studies have identified and validated growth hormone receptor (GHR) expression and growth hormone (GH) action as an oncogenic factor in cancer. Recent studies by us and others have revealed a unique aspect of GH mediated endocrine regulation of pharmacological therapy resistance in human melanoma and breast cancer. GH overexpression was found to not only promote tumor proliferation, migration, and invasion but also associated with refractoriness towards radiation and chemotherapy. However, the underlying mechanisms of the observed GH effects were unknown. To understand the molecular details of therapy resistance of the GH-GHR axis in cancer, we have used four different GHR-positive human cancers of pancreas, kidney, lung, and melanoma. We have identified multi-modal therapy resistance pathways regulated by GH action in these tumors, which was absent in GHR-negative cell lines. Here we report our latest findings explaining the method of action of GH driven cancer therapy resistance and the associated mediators. Expression of GHR and an autocrine / paracrine GH production, elicited specifically by onset of therapy (chemo, targeted, radiation) upregulates (i) ATP-binding cassette containing multidrug efflux pumps, (ii) phenotype switch via epithelial-to-mesenchymal transition, (iii) extracellular matrix rearrangement to promote tumor invasion, and (iv) cytokine mediated immunoediting. Attenuation of the GHR activity using GHR-antagonists or CRISPR-Cas9 mediated GHR knockout severely sensitized the cells towards therapy. In vivo studies using syngeneic mouse models and a thorough analyses of the TCGA data provide robust confirmation to our in vitro findings. Based on the above and ongoing studies in different mouse models of GH action, we speculate that targeting GHR as an adjuvant in cancer therapeutics might synergize therapeutic applications and lead towards a significantly improved prognosis for GHR-positive cancers.