Dataset Information

Activation of Serum/Glucocorticoid Regulated Kinase 1/Nuclear Factor-?B Pathway Are Correlated with Low Sensitivity to Bortezomib and Ixazomib in Resistant Multiple Myeloma Cells.

ABSTRACT: Multiple myeloma (MM) is an incurable malignancy often associated with primary and acquired resistance to therapeutic agents, such as proteasome inhibitors. However, the mechanisms underlying the proteasome inhibitor resistance are poorly understood. Here, we elucidate the mechanism of primary resistance to bortezomib and ixazomib in the MM cell lines, KMS-20, KMS-26, and KMS-28BM. We find that low bortezomib and ixazomib concentrations induce cell death in KMS-26 and KMS-28BM cells. However, high bortezomib and ixazomib concentrations induce cell death only in KMS-20 cells. During Gene Expression Omnibus analysis, KMS-20 cells exhibit high levels of expression of various genes, including anti-phospho-fibroblast growth factor receptor 1 (FGFR1), chemokine receptor type (CCR2), and serum and glucocorticoid regulated kinase (SGK)1. The SGK1 inhibitor enhances the cytotoxic effects of bortezomib and ixazomib; however, FGFR1 and CCR2 inhibitors do not show such effect in KMS-20 cells. Moreover, SGK1 activation induces the phosphorylation of NF-?B p65, and an NF-?B inhibitor enhances the sensitivity of KMS-20 cells to bortezomib and ixazomib. Additionally, high levels of expression of SGK1 and NF-?B p65 is associated with a low sensitivity to bortezomib and a poor prognosis in MM patients. These results indicate that the activation of the SGK1/NF-?B pathway correlates with a low sensitivity to bortezomib and ixazomib, and a combination of bortezomib and ixazomib with an SGK1 or NF-?B inhibitor may be involved in the treatment of MM via activation of the SGK1/NF-?B pathway.

SUBMITTER: Tsubaki M

PROVIDER: S-EPMC7823718 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Activation of Serum/Glucocorticoid Regulated Kinase 1/Nuclear Factor-κB Pathway Are Correlated with Low Sensitivity to Bortezomib and Ixazomib in Resistant Multiple Myeloma Cells.

Tsubaki Masanobu M Takeda Tomoya T Matsuda Takuya T Seki Shiori S Tomonari Yoshika Y Koizumi Shoutaro S Nagatakiya Miki M Katsuyama Mai M Yamamoto Yuuta Y Tsurushima Katsumasa K Ishizaka Toshihiko T Nishida Shozo S

Biomedicines 20210104 1

Multiple myeloma (MM) is an incurable malignancy often associated with primary and acquired resistance to therapeutic agents, such as proteasome inhibitors. However, the mechanisms underlying the proteasome inhibitor resistance are poorly understood. Here, we elucidate the mechanism of primary resistance to bortezomib and ixazomib in the MM cell lines, KMS-20, KMS-26, and KMS-28BM. We find that low bortezomib and ixazomib concentrations induce cell death in KMS-26 and KMS-28BM cells. However, hi ...[more]

PMID: 33406639

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Project description:BackgroundThe ongoing US MM-6 study is investigating in-class transition (iCT) from parenteral bortezomib-based induction to all-oral IRd (ixazomib-lenalidomide-dexamethasone) with the aim of increasing proteasome inhibitor (PI)-based treatment adherence and duration while maintaining patients' health-related quality of life (HRQoL) and improving outcomes.Patients and methodsUS community sites are enrolling non-transplant-eligible patients with newly diagnosed multiple myeloma (MM) with no evidence of progressive disease after 3 cycles of bortezomib-based therapy to receive IRd (up to 39 cycles or until progression or toxicity). The patients use mobile or wearable digital devices to collect actigraphy (activity and sleep) data and electronically complete HRQoL, treatment satisfaction and medication adherence questionnaires. The primary endpoint is progression-free survival. The key secondary endpoints include response rates and therapy duration.ResultsAt the data cutoff, 84 patients had been treated (median age 73 years; 44% aged ≥ 75 years; 49% men; 15% Black or African American; and 10% Hispanic or Latino). Of the 84 patients, 62% were continuing therapy. The mean duration of total PI therapy was 10.1 months and for the IRd regimen was 7.3 months. With an 8-month median follow-up, the 12-month progression-free survival rate was 86% (95% confidence interval, 73%-93%) from both the start of bortezomib-based treatment and the start of IRd. The overall response rate was 62% (complete response, 4%; very good partial response, 25%; partial response, 33%) after bortezomib-based induction and 70% (complete response, 26%; very good partial response, 29%; partial response, 15%) after iCT. The IRd safety profile was consistent with previous clinical trial data, and HRQoL and treatment satisfaction were maintained.ConclusionThe patients included in the US MM-6 study are representative of the real-world US MM population. The use of iCT might permit prolonged PI-based therapy with promising efficacy, without impacting patients' HRQoL or treatment satisfaction.

Dataset Information

Activation of Serum/Glucocorticoid Regulated Kinase 1/Nuclear Factor-?B Pathway Are Correlated with Low Sensitivity to Bortezomib and Ixazomib in Resistant Multiple Myeloma Cells.

Publications

Activation of Serum/Glucocorticoid Regulated Kinase 1/Nuclear Factor-κB Pathway Are Correlated with Low Sensitivity to Bortezomib and Ixazomib in Resistant Multiple Myeloma Cells.

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