Abstract 5850: Nrf2-mediated oxidative stress response is altered during acquired resistance to the proteasome inhibitor, oprozomib, in multiple myeloma

Abstract Multiple myeloma (MM) is a hematologic neoplasm characterized by malignant proliferation of plasma cells in the bone marrow. Proteasome inhibitors are widely used in treatment regimens for MM. Although initial responses to PI (e.g., bortezomib, carfilzomib) treatments have been promising, patients often develop resistance and become refractory to disease. Understanding molecular alterations in signaling cascades influenced by proteasome inhibitors and mechanisms underlying acquired resistance is needed. In this study, we have established a clinically relevant oproxomib-resistant subline (KMS28BMONYX) of the MM cell line KMS28BM. The KMS28BMONYX cell line is pan-resistant to PIs with a 10-fold increase in IC50 for oprozomib as compared to the parental line. To identify genes involved in modulating drug resistance, we analyzed gene expression profiles of both parental and resistant cell lines using the Affymetrix GeneChip Human Genome U133 Plus 2.0 array. Ingenuity Pathway Analysis of microarray data comparing the parental and resistant cells revealed an acute dependence on stress response proteins to maintain PI-resistance. Activation of nuclear factor-erythroid 2 (NF-E2)-related factor 2 (Nrf2; gene symbol NFE2L2) coupled with elevated levels of sequestosome 1/p62 (SQSTM1/p62) were prominent features of the KMS28BMONYX cell line. Altered levels of SQSTM1 correlated with resistance to oprozomib in several MM cell lines. Simultaneously, the KMS28BMONYX cell line showed increased expression of MYC and MCL1. Oprozomib treatment stabilized c-Myc expression in the KMS28BMONYX line. The Champion ChiP Transcription Factor Search Portal database DECODE predicted two c-Myc transcription factor binding sites in the SQSTM1 promoter. CHIP-seq data for MYC in MM1s cells also indicates strong binding in the promoter region of SQSTM1. Our data suggest that therapies targeting the SQSTM1/p62-Nrf2 pathway may help overcome proteasome inhibitor resistance in refractory MM patients. Citation Format: Snehal M. Gaikwad, Adriana Zingone, Aleksandra Michalowski, Susana Najera, Anaisa Quintanilla-Artega, Sayeh Gorjifard, John Simmons, Nick Watson, Ola Landgren, Jing Huang, Beverly Mock. Nrf2-mediated oxidative stress response is altered during acquired resistance to the proteasome inhibitor, oprozomib, in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5850