Long‐term exposure of gastrointestinal stromal tumor cells to sunitinib induces epigenetic silencing of the PTEN gene

Yang, Jing; Ikezoe, Takayuki; Nishioka, Chie; Takezaki, Yuka; Hanazaki, Kazuhiro; Taguchi, Takahiro; Yokoyama, Akihito

doi:10.1002/ijc.26095

Cited by 39 publications

(30 citation statements)

References 40 publications

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“…As revealed by RT-qPCR analysis, PTEN loss was associated with substantially lower or absent PTEN transcript levels (P ¼ 0.002). In contrast to Yang et al, 18 we do not have evidence that receptor tyrosine kinase inhibitor treatment can cause loss of PTEN expression by epigenetic silencing, as we did not identify PTEN promoter methylation in any of the analyzed imatinib-resistant GIST. This finding together with the lack of evidence for inactivation of the PTEN by inactivating mutations suggests that the aberrantly low PTEN expression in GIST might be mainly due to mono-allelic loss.…”

Section: Discussioncontrasting

confidence: 99%

Frequent mono-allelic loss associated with deficient PTEN expression in imatinib-resistant gastrointestinal stromal tumors

et al. 2014

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Insufficiency of phosphatase and tensin homolog (PTEN) occurs in numerous tumor types and has been implicated as a resistance mechanism to receptor tyrosine kinase-targeted therapies in human cancer. In this study, we have performed a comprehensive molecular and immunohistochemical characterization of PTEN in 58 imatinib-naı¨ve and 54 imatinib-treated gastrointestinal stromal tumors (GISTs). The findings were correlated with clinicopathological data. At the genomic level, PTEN was affected mainly by mono-allelic loss, which was significantly less frequent in imatinib-naı¨ve vs imatinib-resistant tumors (9% vs 39%, Po0.001). Neither PTEN mutations nor PTEN promoter hyper-methylation were found. By immunohistochemistry, PTEN depletion was clearly related to GIST progression. Low PTEN protein expression was common (50%) and often paralleled with total immunonegativity in imatinib-resistant tumors. The abnormal PTEN protein expression correlated with PTEN loss at the genomic level (P ¼ 0.001). In addition, the effect of small interfering RNA (siRNA) PTEN knockdown on KIT signaling was examined in GIST-T1 and GIST430 cell lines, in the absence or presence of a dual PI3K/mTOR inhibitor NVP-BEZ235, alone or in combination with imatinib. In both cell lines, siRNA silencing of PTEN resulted in the substantial upregulation of PI3K-AKT and MAPK pathways. The MAPK hyperactivation was further potentiated by NVP-BEZ235 in the imatinib-sensitive GIST-T1 cells; yet, this effect was counteracted efficiently by combined treatment. In the imatinib-resistant GIST430 cells, neither NVP-BEZ235 alone or in combination with imatinib yielded sufficient inhibition of hyper-phosphorylated MAPK and downstream intermediate S6 protein. In conclusion, depleted PTEN expression associated with mono-allelic PTEN loss occurs frequently in imatinib-resistant GIST and might serve as a biomarker for stratifying patients for optimal treatment. In vitro, the PTEN insufficiency leads to hyperactivation of AKT and MAPK pathways in tumor cells. Novel therapies targeting multiple components of the integrated KIT receptor signaling pathways in imatinibresistant GIST warrant further studies.

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Section: Discussioncontrasting

confidence: 99%

Frequent mono-allelic loss associated with deficient PTEN expression in imatinib-resistant gastrointestinal stromal tumors

et al. 2014

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“…Even though there is an urgent need to understanding the mechanisms underlying acquired sunitinib resistance, only a handful of experimental studies have been performed to date. A diversity of mechanisms underlying the sunitinib-resistance phenotype has been elucidated under different experimental conditions, including various in vitro and/or in vivo approaches using different tumor cell lines (Huang et al, 2010;Gotink et al, 2011;Kutikov et al, 2011;Bender and Ullrich, 2012;Yang et al, 2012). Each individual study has focused merely on one aspect of resistance, either a distinct proangiogenic factor, a prosurvival signaling pathway (Huang et al, 2010;Kutikov et al, 2011;Bender and Ullrich, 2012;Yang et al, 2012), or lysosomal sequestration (Gotink et al, 2011); thus, in-depth knowledge about the mechanisms involved in acquired sunitinib resistance is still lacking.…”

Section: Introductionmentioning

confidence: 99%

Activation of Alternate Prosurvival Pathways Accounts for Acquired Sunitinib Resistance in U87MG Glioma Xenografts

Zhou

Mazloom

et al. 2012

J Pharmacol Exp Ther

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Acquired drug resistance represents a major obstacle to using sunitinib for the treatment of solid tumors. Here, we examined the cellular and molecular alterations in tumors that are associated with acquired brain tumor resistance to sunitinib by using an in vivo model. U87MG tumors obtained from nude mice that received sunitinib (40 mg/kg/day) for 30 days were classified into sunitinib-sensitive and -resistant groups based on tumor volume and underwent targeted gene microarray and protein array analyses. The expression of several angiogenesisassociated genes was significantly modulated in sunitinibtreated tumors compared with those in control tumors (p Ͻ 0.05), whereas no significant differences were observed between sunitinib-sensitive and -resistant tumors (p Ͼ 0.05). Tumor vasculature based on microvessel density, neurogenin 2 chondroitin sulfate proteoglycan density, and ␣-smooth muscle actin density was also similar in sunitinib-treatment groups (p Ͼ 0.05). The moderate increase in unbound sunitinib tumor-toplasma area-under-the-curve ratio in sunitinib-resistant mice was accompanied by up-regulated ATP-binding cassette G2 expression in tumor. The most profound difference between the sunitinib-sensitive and -resistant groups was found in the expression of several phosphorylated proteins involved in intracellular signaling. In particular, phospholipase C-␥1 phosphorylation in sunitinib-resistant tumors was up-regulated by 2.6-fold compared with that in sunitinib-sensitive tumors (p Ͻ 0.05). In conclusion, acquired sunitinib resistance in U87MG tumors is not associated with revascularization in tumors, but rather with the activation of alternate prosurvival pathways involved in an escape mechanism facilitating tumor growth and possibly insufficient drug uptake in tumor cells caused by an up-regulated membrane efflux transporter.

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“…In addition, phosphatase and a tensin homolog deleted from chromosome 10 (PTEN) opposes the phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway and acts as a tumor suppressor. Growth signaling is constitutively activated in PTEN-deficient 786-O cells (Huang et al, 2010;Makhov et al, 2012;Yang et al, 2012;Chang et al, 2013). Accordingly, it is possible that 786-O cells displayed a lower sensitivity to sunitinib than the other cell lines.…”

Section: Discussionmentioning

confidence: 99%

Induction of Epithelial-Mesenchymal Transition via Activation of Epidermal Growth Factor Receptor Contributes to Sunitinib Resistance in Human Renal Cell Carcinoma Cell Lines

Mizumoto

Yamamoto

Nakayama

et al. 2015

J Pharmacol Exp Ther

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Sunitinib is widely used for treating renal cell carcinoma (RCC). However, some patients do not respond to treatment with this drug. We aimed to study the association between sunitinib sensitivity and epithelial-mesenchymal transition (EMT) regulation via epidermal growth factor receptor (EGFR) signaling, which is a mechanism of resistance to anticancer drugs. Three RCC cell lines (786-O, ACHN, and Caki-1) were used, and then we evaluated cell viability, EMT regulatory proteins, and signal transduction with sunitinib treatment. Cell viability of 786-O cells was maintained after treatment with sunitinib. After treatment with sunitinib, EGFR phosphorylation increased in 786-O cells, resulting in an increase in the phosphorylation of extracellular signal-regulated kinase, nuclear translocation of b-catenin, and expression of mesenchymal markers. These results suggest that sunitinib induced EMT via activation of EGFR in 786-O cells, but not in ACHN and Caki-1 cells. Caki-1/SN cells, a resistant cell line generated by continuous exposure to sunitinib, displayed increased phosphorylation of EGFR. Cell viability in the presence of sunitinib was decreased by erlotinib, as the selective inhibitor of EGFR, treatment in 786-O and Caki-1/SN cells. Similarly, erlotinib suppressed sunitinib-induced EGFR activation and upregulated mesenchymal markers. Thus, we postulate that resistance to sunitinib in RCC may be associated with EMT caused by activation of EGFR.

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Long‐term exposure of gastrointestinal stromal tumor cells to sunitinib induces epigenetic silencing of the PTEN gene

Cited by 39 publications

References 40 publications

Frequent mono-allelic loss associated with deficient PTEN expression in imatinib-resistant gastrointestinal stromal tumors

Frequent mono-allelic loss associated with deficient PTEN expression in imatinib-resistant gastrointestinal stromal tumors

Activation of Alternate Prosurvival Pathways Accounts for Acquired Sunitinib Resistance in U87MG Glioma Xenografts

Induction of Epithelial-Mesenchymal Transition via Activation of Epidermal Growth Factor Receptor Contributes to Sunitinib Resistance in Human Renal Cell Carcinoma Cell Lines

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