Activation of ERK1/2 Causes Pazopanib Resistance via Downregulation of DUSP6 in Synovial Sarcoma Cells

Yokoyama, Nobuhiko; Matsunobu, Tomoya; Matsumoto, Yoshihiro; Fukushi, Jun Ichi; Hatano, Masakazu; Nabeshima, Akira; Fukushima, Sunao; Okada, Seiji; Iwamoto, Yukihide

doi:10.1038/srep45332

Cited by 9 publications

(8 citation statements)

References 47 publications

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“…To address the role of ERKs activation in pazopanib resistant MoJo cells, we analyzed expression of the ERK-specific phosphatase MKP3 (DUSP6). Indeed, enhanced ERK activation has been recently associated with in vitro acquired SS resistance to pazopanib as a consequence of MKP3 downregulation [21]. Conversely, we found MKP3 markedly overexpressed in MoJo compared to SYO-1 cells and not detectable in CME-1 cells (Figure 4A).…”

Section: Resultsmentioning

confidence: 48%

“…Moreover, the high levels of the ERK-specific MKP3 phosphatase, which is transcriptionally induced by ERK, reflected an enhanced negative feedback required to avoid growth arrest or cell death caused by excessive ERK activation [47]. It is noteworthy that, in apparent contrast with our data, reduced MKP3 levels, also enhancing ERK activation, have been associated with in vitro acquired pazopanib resistance [21]. Convergence on ERK pathway activation of different mechanisms of intrinsic and acquired resistance underlines the relevance of this signaling axis in the modulation of SS cell sensitivity to the drug.…”

Section: Discussionmentioning

confidence: 55%

“…Similar to other clinically available targeted therapies, the occurrence of pazopanib resistance is frequent even in initially responsive patients, underlying the need to identify mechanisms of intrinsic and acquired drug resistance and to develop appropriate patient selection criteria and drug combination strategies to improve treatment outcome. Recent preclinical evidence indicates that resistance to pazopanib treatment can occur in SS cells through various mechanisms, including activating mutations of receptor tyrosine kinase (RTK) genes found with low frequency in SS, or by an adaptive cell kinome reprogramming following prolonged exposure to the drug [17,20,21,22].…”

Section: Introductionmentioning

confidence: 99%

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Overactive IGF1/Insulin Receptors and NRASQ61R Mutation Drive Mechanisms of Resistance to Pazopanib and Define Rational Combination Strategies to Treat Synovial Sarcoma

Lanzi

Favini

et al. 2019

Cancers

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Pazopanib is approved for treatment of advanced soft tissue sarcomas, but primary and secondary drug resistance limits its clinical utility. We investigated the molecular mechanisms mediating pazopanib resistance in human synovial sarcoma (SS) models. We found reduced cell sensitivity to pazopanib associated with inefficient inhibition of the two critical signaling nodes, AKT and ERKs, despite strong inhibition of the main drug target, PDGFRα. In the CME-1 cell line, overactivation of IGF1 and Insulin receptors (IGF1R/InsR) sustained AKT activation and pazopanib resistance, which was overcome by a combination treatment with the double IGF1R/InsR inhibitor BMS754807. In the highly pazopanib resistant MoJo cell line, NRASQ61R mutation sustained constitutive ERK activation. Transfection of the NRAS mutant in the pazopanib sensitive SYO-1 cell line increased the drug IC50. MoJo cells treatment with pazopanib in combination with the MEK inhibitor trametinib restored ERK inhibition, synergistically inhibited cell growth, and induced apoptosis. The combination significantly enhanced the antitumor efficacy against MoJo orthotopic xenograft abrogating growth in 38% of mice. These findings identified two different mechanisms of intrinsic pazopanib resistance in SS cells, supporting molecular/immunohistochemical profiling of tumor specimens as a valuable approach to selecting patients who may benefit from rational drug combinations.

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Section: Resultsmentioning

confidence: 48%

Section: Discussionmentioning

confidence: 55%

Section: Introductionmentioning

confidence: 99%

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Overactive IGF1/Insulin Receptors and NRASQ61R Mutation Drive Mechanisms of Resistance to Pazopanib and Define Rational Combination Strategies to Treat Synovial Sarcoma

Lanzi

Favini

et al. 2019

Cancers

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“…Erk1/2 is an important component of the cascade of Ras-Raf-MEK-ERK signaling pathway, which has received extensive attention in tumor resistance and tumor therapy [27][28][29]. It is activated in many cisplatin treated cell lines [30][31][32][33]. In the resting state, ERK1/2 binds to MEK in the cytoplasm.…”

Section: Discussionmentioning

confidence: 99%

Low expression of NCALD is associated with chemotherapy resistance and poor prognosis in epithelial ovarian cancer

Feng

2020

J Ovarian Res

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Background: Low expression of NCALD(neurocalcin delta) in peripheral blood of ovarian cancer patients predicts poor prognosis. However, the molecular mechanism of NCALD in ovarian cancer and its relationship with chemotherapy outcomes is unclear. The aim of this study was to investigate the potential signaling pathways of NCALD and to evaluate its ability to predict chemotherapy outcomes and prognosis. Methods: High-throughput RNA sequencing data were downloaded from TCGA. GSEA explored the potential signaling pathways of NCALD. The expression of NCALD in chemotherapy sensitive and chemotherapy resistant ovarian cancer patients was detected by TCGA data and clinical samples. ROC analysis confirmed the ability of NCALD to predict chemotherapy outcomes. The association between NCALD expression and prognosis in ovarian cancer patients was assessed using Kaplan-Meier plotter. Results: In patients with NCALD overexpression, genes expression related to ERK1 / 2 signaling pathway, NF-kappaB signaling pathway, TGF-β signaling pathway and immune response pathway was increased, especially ERK1 / 2 signaling pathway. The expression of NCALD in chemoresistant patients was significantly lower than chemosensitive patients. In TCGA data and immunohistochemical samples, the AUC of NCALD expression predicting chemotherapy outcome was 0.59 and 0.64, respectively. In clinical samples, low expression of NCALD was associated with poor OS and PFS. Conclusions: NCALD may activate the ERK1 / 2 signaling pathway in ovarian cancer. As a new biomarker of chemotherapy sensitivity, NCALD was significantly down-regulated in chemotherapy resistance ovarian cancer patients. Low expression of NCALD in ovarian cancer is associated with poor OS and PFS. In the future, further research will be needed on the potential mechanism and clinical application value of NCALD in ovarian cancer.

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“…Another possible strategy for cancer treatment is to reverse or replace DUSP6 function. For example, Yokoyama et al 118 demonstrated that increased ERK1/2 expression and downregulated DUSP6 caused pazopanib resistance in synovial sarcoma cells. Hence, simultaneous treatment with pazopanib and a MEK inhibitor would be a good strategy to overcome resistance.…”

Section: Frontiersmentioning

confidence: 99%

Dual-specificity phosphatase 6 (DUSP6): a review of its molecular characteristics and clinical relevance in cancer

Ahmad

Abdollah

Shafie

et al. 2018

Cancer Biology & Medicine

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Mitogen-activated protein kinases (MAPKs) are the main regulators of cellular proliferation, growth, and survival in physiological or pathological conditions. Aberrant MAPK signaling plays a pivotal role in carcinogenesis, which leads to development and progression of human cancer. Dual-specificity phosphatase 6 (DUSP6), a member of the MAPK phosphatase family, interacts with specifically targeted extracellular signal-regulated kinase 1/2 via negative feedback regulation in the MAPK pathway of mammalian cells. This phosphatase functions in a dual manner, pro-oncogenic or tumor-suppressive, depending on the type of cancer. To date, the tumor-suppressive role of DUSP6 has been demonstrated in pancreatic cancer, non-small cell lung cancer, esophageal squamous cell and nasopharyngeal carcinoma, and ovarian cancer. Its pro-oncogenic role has been observed in human glioblastoma, thyroid carcinoma, breast cancer, and acute myeloid carcinoma. Both roles of DUSP6 have been documented in malignant melanoma depending on the histological subtype of the cancer. Loss- or gain-of-function effects of DUSP6 in these cancers highlights the significance of this phosphatase in carcinogenesis. Development of methods that use the DUSP6 gene as a therapeutic target for cancer treatment or as a prognostic factor for diagnosis and evaluation of cancer treatment outcome has great potential. This review focuses on molecular characteristics of the DUSP6 gene and its role in cancers in the purview of development, progression, and cancer treatment outcome.

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Activation of ERK1/2 Causes Pazopanib Resistance via Downregulation of DUSP6 in Synovial Sarcoma Cells

Cited by 9 publications

References 47 publications

Overactive IGF1/Insulin Receptors and NRASQ61R Mutation Drive Mechanisms of Resistance to Pazopanib and Define Rational Combination Strategies to Treat Synovial Sarcoma

Overactive IGF1/Insulin Receptors and NRASQ61R Mutation Drive Mechanisms of Resistance to Pazopanib and Define Rational Combination Strategies to Treat Synovial Sarcoma

Low expression of NCALD is associated with chemotherapy resistance and poor prognosis in epithelial ovarian cancer

Dual-specificity phosphatase 6 (DUSP6): a review of its molecular characteristics and clinical relevance in cancer

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