PTTG1 Levels Are Predictive of Saracatinib Sensitivity in Ovarian Cancer Cell Lines

Nakachi, Ichiro; Helfrich, Barbara A.; Spillman, Monique A.; Mickler, Elizabeth A.; Olson, Chelsea J.; Rice, Jessica L.; Coldren, Chris D.; Heasley, Lynn E.; Geraci, Mark W.; Stearman, Robert S.

doi:10.1111/cts.12413

Cited by 17 publications

(14 citation statements)

References 45 publications

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“…The mean expression level of FOXM1 was previously reported to be the highest in the TNBC subtype, which was associated with poor prognosis and reduced survival time in patients with breast cancer (29,30). Notably, PTTG1 is an oncogene that is important for the progression of mitosis in the metaphase-anaphase transition (31,32). Additionally, PTTG1 overexpression is associated with malignancy, particularly thyroid, breast and colorectal carcinoma (32).…”

Section: Discussionmentioning

confidence: 99%

High WDR34 mRNA expression as a potential prognostic biomarker in patients with breast cancer as determined by integrated bioinformatics analysis

Shi

et al. 2019

Oncol Lett

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The WD-repeat domain (WDR) family is distributed in the majority of eukaryotes and has several unique biological functions. It serves important roles in signal transduction, cytoskeleton assembly, protein transport, RNA processing, chromatin modification and transcription mechanisms. WD repeat domain 34 (WDR34) has been recently identified as a member of the WDR family. Overexpression of WDR34 was accompanied by the presence of multiple centrioles in the cell, suggesting that it was associated with tumor occurrence. However, its association with breast cancer was unclear. To the best of our knowledge, it has not yet been confirmed whether WDR34 gene expression is associated with breast cancer. Therefore, the current study attempted to clarify this by performing a comprehensive study using multiple datasets in the Oncomine, Breast Cancer Gene-Expression Miner and Kaplan-Meier Plotter databases. The analysis indicated that the mRNA expression levels of WDR34 were increased in breast cancer tissues compared with normal tissues. Consistent with this result, the Broad-Novartis Cancer Cell Line Encyclopedia revealed that WDR34 mRNA expression levels were upregulated in breast cancer cell lines compared with other cancer cells. It was noted that high WDR34 mRNA expression was associated with forkhead box M1 and PTTG1 regulator of sister chromatid separation, securing in co-expression analysis. Expression profile characteristics of WDR34 mRNA were identified in different molecular subtypes of breast cancer. Furthermore, survival analysis revealed that increased expression levels of WDR34 mRNA were associated with poor overall survival in patients with breast cancer, particularly in luminal B, lymph node status-positive and estrogen receptor (ER)-negative subgroups. Additionally, Kaplan-Meier curves revealed that high WDR34 mRNA expression was associated with shorter relapse-free survival in patients with breast cancer, particularly in ER-positive, human epidermal growth factor receptor 2-negative and progesterone receptor-positive subgroups. These results suggested that WDR34 may be used as a prognosis predictor in breast cancer and may provide a novel target for the diagnosis and treatment of breast cancer.

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Section: Discussionmentioning

confidence: 99%

High WDR34 mRNA expression as a potential prognostic biomarker in patients with breast cancer as determined by integrated bioinformatics analysis

Shi

et al. 2019

Oncol Lett

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“…In breast cancer, PTTG1 was among the eight genes significantly overexpressed in tumor specimens of patients who relapsed on tamoxifen treatment as compared with tumor of patients who did not [ 27 ]. Furthermore, high levels of PTTG1 were found to promote resistance to gefitinib-induced apoptosis in various tumor cell lines [ 28 ] and to be associated with saracatinib resistance in ovarian cancer cells [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

Targeting the PTTG1 oncogene impairs proliferation and invasiveness of melanoma cells sensitive or with acquired resistance to the BRAF inhibitor dabrafenib

et al. 2017

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The pituitary tumor transforming gene 1 (PTTG1) is implicated in tumor growth, metastasis and drug resistance. Here, we investigated the involvement of PTTG1 in melanoma cell proliferation, invasiveness and response to the BRAF inhibitor (BRAFi) dabrafenib. We also preliminary assessed the potential value of circulating PTTG1 protein to monitor melanoma patient response to BRAFi or to dabrafenib plus trametinib. Dabrafenib-resistant cell lines (A375R and SK-Mel28R) were more invasive than their drug-sensitive counterparts (A375 and SK-Mel28), but expressed comparable PTTG1 levels. Dabrafenib abrogated PTTG1 expression and impaired invasion of the extracellular matrix (ECM) in A375 and SK-Mel28 cells. In contrast, it affected neither PTTG1 expression in A375R and SK-Mel28R cells, nor ECM invasion in the latter cells, while further stimulated A375R cell invasiveness. Assessment of proliferation and ECM invasion in control and PTTG1-silenced A375 and SK-Mel28 cells, exposed or not to dabrafenib, demonstrated that the inhibitory effects of this drug were, at least in part, dependent on its ability to down-regulate PTTG1 expression. PTTG1-silencing also impaired proliferation and invasiveness of A375R and SK-Mel28R cells, and counteracted dabrafenib-induced stimulation of ECM invasion in A375R cells. Further experiments performed in A375R cells indicated that PTTG1-silencing impaired cell invasiveness through inhibition of MMP-9 and that PTTG1 expression and ECM invasion could be also reduced by the CDK4/6 inhibitor LEE011. PTTG1 targeting might, therefore, represent a useful strategy to impair proliferation and metastasis of melanomas resistant to BRAFi. Circulating PTTG1 also appeared to deserve further investigation as biomarker to monitor patient response to targeted therapy.

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“…Multiple studies have identified a number of mechanisms of resistance to inhibitors of the SRC pathway including activation of the mTOR pathway [ 19 ], suppression of autophagy [ 20 ] and secondary mutations in DDR , as well as loss of the tumour suppressor gene NF1 [ 21 ]. It has also been reported that PTTG1 expression is predictive of sensitivity in ovarian cancer cell lines to SRC inhibition with saractinib (AZD0530) [ 22 ]. However this work has not been performed in ovarian cancer models of acquired resistance to SRC inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Activation of MAPK signalling results in resistance to saracatinib (AZD0530) in ovarian cancer

et al. 2017

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SRC tyrosine kinase is frequently overexpressed and activated in late-stage, poor prognosis ovarian tumours, and preclinical studies have supported the use of targeted SRC inhibitors in the treatment of this disease. The SAPPROC trial investigated the addition of the SRC inhibitor saracatinib (AZD0530) to weekly paclitaxel for the treatment of platinum resistant ovarian cancer; however, this drug combination did not provide any benefit to progression free survival (PFS) of women with platinum resistant disease. In this study we aimed to identify mechanisms of resistance to SRC inhibitors in ovarian cancer cells. Using two complementary strategies; a targeted tumour suppressor gene siRNA screen, and a phospho-receptor tyrosine kinase array, we demonstrate that activation of MAPK signalling, via a reduction in NF1 (neurofibromin) expression or overexpression of HER2 and the insulin receptor, can drive resistance to AZD0530. Knockdown of NF1 in two ovarian cancer cell lines resulted in resistance to AZD0530, and was accompanied with activated MEK and ERK signalling. We also show that silencing of HER2 and the insulin receptor can partially resensitize AZD0530 resistant cells, which was associated with decreased phosphorylation of MEK and ERK. Furthermore, we demonstrate a synergistic effect of combining SRC and MEK inhibitors in both AZD0530 sensitive and resistant cells, and that MEK inhibition is sufficient to completely resensitize AZD0530 resistant cells. This work provides a preclinical rationale for the combination of SRC and MEK inhibitors in the treatment of ovarian cancer, and also highlights the need for biomarker driven patient selection for clinical trials.

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PTTG1 Levels Are Predictive of Saracatinib Sensitivity in Ovarian Cancer Cell Lines

Cited by 17 publications

References 45 publications

High WDR34 mRNA expression as a potential prognostic biomarker in patients with breast cancer as determined by integrated bioinformatics analysis

High WDR34 mRNA expression as a potential prognostic biomarker in patients with breast cancer as determined by integrated bioinformatics analysis

Targeting the PTTG1 oncogene impairs proliferation and invasiveness of melanoma cells sensitive or with acquired resistance to the BRAF inhibitor dabrafenib

Activation of MAPK signalling results in resistance to saracatinib (AZD0530) in ovarian cancer

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