THU549 Targeting The Growth Hormone Receptor Attenuates Tumor Exosome Mediated Propagation Of Chemoresistance In Melanoma

Abstract

Abstract Disclosure: P. Kulkarni: None. R. Basu: None. T. Bonn: None. J.J. Kopchick: None. Elevated ATP-binding cassette (ABC) transporters in tumor cells resulting in decreased intracellular drug accumulation is a major reason for chemotherapy resistance in cancer. Mounting evidence indicates that extracellular vesicles (EVs), particularly exosomes, the smallest subset of EVs, play a crucial role in the spread of drug resistance. We have previously shown that growth hormone (GH) decreases therapeutic efficacy in melanoma via upregulating the levels of ABC transporters, whereas when GHR is knocked down or GH/GHR interaction is inhibited by GHR antagonist, Pegvisomant, these ABC transporters are significantly downregulated. No study has yet directly assessed the effect of GH or GHR antagonism on exosomal cargoes in terms of promoting drug resistance. We observe that human melanoma cells (Malme3M, SK-Mel28, and MDA-MB-435) when treated with GH or doxorubicin alone or in combination increase the exosomal protein levels of multiple multi-drug efflux pumps, namely ABCC1, ABCC2, ABCB1, and ABCG2. On adding Pegvisomant to these treatments, we found a significant decrease in the levels of these exosomal drug efflux pumps induced by both autocrine and endogenously added GH. Furthermore, we assessed the role of GH in exosome-mediated dissemination of chemoresistance from drug-resistant to drug-sensitive cells. When GH and doxorubicin-treated melanoma-derived exosomes were administered to treatment-naïve melanoma cells, a significant increase in drug efflux was observed in the latter, compared to the control. On the other hand, when Pegvisomant co-treated melanoma-derived exosomes were administered to treatment-naïve melanoma cells, the drug efflux was attenuated, indicating chemo-sensitization. Collectively, these observations indicate that Pegvisomant suppresses various exosomal cargoes modulating drug resistance in melanoma. Acknowledgment: This work was supported in part by the State of Ohio’s Eminent Scholar Program includes a gift from Milton and Lawrence Goll, by the AMVETS, Ohio University’s Student Enhancement Award, and Edison Biotechnology Institute. Presentation: Thursday, June 15, 2023