Abstract 2106: Role of organic cation transporter-1 (OCT-1) in drug resistance condition of ph+ chronic myeloid leukemia (CML)

Abstract

Abstract A solute carrier (SLC) superfamily member, a major influx protein Organic Cation Transporter-1 (OCT-1), reported to be involved in influx of the Imatinib and other drugs in target cells. Despite the excellent responses to Imatinib and other tyrosine kinase inhibitors (TKIs) in CML, around a quarter of patients demonstrate primary resistance or suboptimal response within one year of therapy. Hence, present study mainly emphases the possible translocation mechanism of Imatinib, major TKIs and other chemotherapeutic agents that is mediated by OCT-1 transporter and OCT-1 gene expression level in progressive phases of CML. Homology based comparative modeling of OCT-1 protein, and its in-depth systemic interaction binding pattern analysis with Imatinib and other TKIs were conducted using computational modeling and molecular dynamics studies, respectively. Quantitative expression analysis of OCT-1 has also been evaluated in patients receiving Imatinib alone, hydroxyurea alone or both drug in different CML phases such as chronic, accelerated and blastic crisis phases for both in bone marrow and PBMNC samples (n=120). The interaction profile of Imatinib with OCT-1 revealed major conformational between ligand and protein interaction sites. However, generated protein-ligand complexes proceeded for molecular dynamics studies (100ns) that have confirmed the selectivity of Imatinib and other drugs towards the OCT-1 and possible translocation path of ligands in the OCT-1 cavities. In quantitative gene expression analysis, downregulation of OCT-1 expression as evident by decreased fold change values in patients with blastic crisis compared to chronic phase responsible for lower uptake of Imatinib into the cells. Hence, cells can not achieve optimum Imatinib inhibitory concentration which may be responsible for disease progression and ultimately leads to drug resistance. Thus, proposed combined computational and experimental approaches suggests OCT-1 mediated activation of bcr-abl independent mechanism, which may be potential confounder of developing Imatinib resistance in CML patients. Citation Format: Saumya Patel, Krupa Shah, Rakesh Rawal. Role of organic cation transporter-1 (OCT-1) in drug resistance condition of ph+ chronic myeloid leukemia (CML) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2106.