KIT oncogenic signaling mechanisms in imatinib-resistant gastrointestinal stromal tumor: PI3-kinase/AKT is a crucial survival pathway

Bauer, Sebastian; Duensing, Anette; Demetri, George D.; Fletcher, Jonathan A.

doi:10.1038/sj.onc.1210558

Cited by 232 publications

(231 citation statements)

References 27 publications

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“…Although these inhibitors have revolutionized the treatment of GIST and other malignancies, management of intrinsic and acquired resistance mechanisms remain a clinical challenge. Activation of the PI3K/AKT pathway, downstream of activated RTKs, has been shown to both predict and promote resistance to RTK inhibitors in GIST and in other malignancies (7,9,10,39-41). Clinical trials are currently underway to investigate the use of PI3K/AKT inhibitors in combination with RTK inhibitors in CLL, melanoma, and NSCLC.…”

Section: Discussionmentioning

confidence: 99%

“…Functional and correlative studies in GIST cell lines and patient samples have established that the PI3-kinase/AKT pathway is critical to survival in IM-resistant GIST (7-11). Recently, a mathematical approach applied to the evolutionary dynamics of solid tumors in response to treatment emphasized the need for concurrently targeting different pathways, or different parts of a pathway, to prevent the establishment of disease resistant to individual drugs (12).…”

Section: Introductionmentioning

confidence: 99%

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Combination of Imatinib Mesylate and AKT Inhibitor Provides Synergistic Effects in Preclinical Study of Gastrointestinal Stromal Tumor

Zook

Pathak

Belinsky

et al. 2017

Clinical Cancer Research

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Purpose Gastrointestinal stromal tumors (GIST) generally harbor activating mutations in the receptor tyrosine kinase KIT or in the related platelet derived growth factor receptor alpha (PDGFRA). GIST treated with imatinib mesylate (IM) or second-line therapies that target mutant forms of these receptors generally escape disease control and progress over time. Inhibiting additional molecular targets may provide more substantial disease control. Recent studies have implicated the PI3-kinase/AKT pathway in the survival of IM-resistant GIST cell lines and tumors. Experimental Design Here, we performed in vitro and in vivo studies evaluating the novel combination of IM with the AKT inhibitor MK-2206 in GIST. Whole-transcriptome sequencing (WTS) of xenografts was performed to explore the molecular aspects of tumor response to this novel combination and to potentially identify additional therapeutic targets in GIST. Results This drug combination demonstrated significant synergistic effects in a panel of IM-sensitive and -resistant GIST cell lines. Furthermore, combination therapy provided significantly greater efficacy, as measured by tumor response and animal survival, in IM-sensitive GIST xenografts as compared to treatment with IM or MK-2206 alone. WTS implicated two neural genes, brain expressed X-linked 1 (BEX1) and neuronal pentraxin I (NPTX1), whose expression was significantly up-regulated in combination-treated tumors compared to tumors treated with the two monotherapies. Conclusion These studies provide strong preclinical justification for combining IM with an AKT inhibitor as a front-line therapy in GIST. In addition, the WTS implicated the BCL-2/BAX/BAD apoptotic pathway as a potential mechanism for this enhanced combination effect.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Combination of Imatinib Mesylate and AKT Inhibitor Provides Synergistic Effects in Preclinical Study of Gastrointestinal Stromal Tumor

Zook

Pathak

Belinsky

et al. 2017

Clinical Cancer Research

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“…Therefore, KIT/ PDGFRA inhibition by small-molecule kinase inhibitors such as imatinib mesylate or sunitinib malate has become the mainstay of treatment in patients with inoperable GIST. At the same time, studies of human GIST cell lines and transgenic mouse models have enabled substantial advances in understanding the central roles of KIT/PDGFRA signaling pathways in GIST cell proliferation and survival (Demetri et al, 2002;Heinrich et al, 2003;Duensing et al, 2004b;Corless et al, 2005;Rossi et al, 2006;Bauer et al, 2007;Zhu et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…These studies evaluated phosphorylation of AKT and mitogen-activated protein kinase (MAPK), among other signaling intermediates that have been shown to be KIT dependent in GISTs Duensing et al, 2004b;Bauer et al, 2007). Evaluations at 4 days after lentiviral shRNA infection showed that KIT silencing resulted in dramatic inactivation of AKT and S6 in the imatinib-resistant GIST48 and GIST430 cells, whereas MAPK was inactivated partially only in GIST430 (Figure 2c).…”

Section: Pkcy Regulates Kit Oncoprotein Expressionmentioning

confidence: 99%

Protein kinase C-θ regulates KIT expression and proliferation in gastrointestinal stromal tumors

Zhu

Demetri

et al. 2008

Oncogene

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“…The PI3K/AKT/mTOR signaling pathway represents a crucial driving force for the growth, survival, and progression of GIST. 8 In human malignancies, PTEN inactivation or insufficiency constitutively activates this pathway. 9 Thereby, GIST patients with PTEN deficiency could benefit from alternative therapies targeting the PI3K/AKT/mTOR pathway.…”

mentioning

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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KIT oncogenic signaling mechanisms in imatinib-resistant gastrointestinal stromal tumor: PI3-kinase/AKT is a crucial survival pathway

Cited by 232 publications

References 27 publications

Combination of Imatinib Mesylate and AKT Inhibitor Provides Synergistic Effects in Preclinical Study of Gastrointestinal Stromal Tumor

Combination of Imatinib Mesylate and AKT Inhibitor Provides Synergistic Effects in Preclinical Study of Gastrointestinal Stromal Tumor

Protein kinase C-θ regulates KIT expression and proliferation in gastrointestinal stromal tumors

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

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