Inhibition of mTORC2/RICTOR Impairs Melanoma Hepatic Metastasis

Schmidt, Katharina; Dietrich, Péter; Hackl, Christina; Guenzle, Jessica; Bronsert, Peter; Wagner, Christine; Fichtner‐Feigl, Stefan; Geissler, Edward K.; Hellerbrand, Claus; Lang, Sven A.

doi:10.1016/j.neo.2018.10.001

Cited by 24 publications

(23 citation statements)

References 59 publications

(92 reference statements)

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“…Interestingly, MMP2 has been shown to be regulated at least in part via mTORC2/Akt signaling [13,14]. With regards to liver metastasis, we have previously pointed out the significance of mTORC2/Rictor in melanoma and pancreatic cancer models by using RNA interference [15]. In the meantime, a pharmacological inhibitor has been developed with potential clinical application, extending our previous work.…”

Section: Introductionmentioning

confidence: 67%

“…Hence, dual kinase inhibitors for PI3K signaling and the rapamycin-sensitive mTORC1 pathway, as well as ATP-competitive inhibitors of mTORC1/2, were assessed in preclinical and clinical settings with limited efficacy [24][25][26]. However, selective inhibition of mTORC2/Rictor in cancer is commonly evaluated using RNAi approaches due to the lack of specific inhibitors so far [15,27,28]. Interestingly, recent work from Benavides-Serrato and coworkers described for the first time the use of a specific pharmacological mTORC2 inhibitor (JR-AB2-011) that was identified from a NCI/DTP small molecule compound library in an experimental glioblastoma model [29].…”

Section: Introductionmentioning

confidence: 99%

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Pharmacological Inhibition of mTORC2 Reduces Migration and Metastasis in Melanoma

Guenzle

Akasaka

Joechle

et al. 2020

IJMS

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Despite recent advances in therapy, liver metastasis from melanoma is still associated with poor prognosis. Although targeting the mTOR signaling pathway exerts potent anti-tumor activity, little is known about specific mTORC2 inhibition regarding liver metastasis. Using the novel mTORC2 specific inhibitor JR-AB2-011, we show significantly reduced migration and invasion capacity by impaired activation of MMP2 in melanoma cells. In addition, blockade of mTORC2 induces cell death by non-apoptotic pathways and reduces tumor cell proliferation rate dose-dependently. Furthermore, a significant reduction of liver metastasis was detected in a syngeneic murine metastasis model upon therapy with JR-AB2-011 as determined by in vivo imaging and necropsy. Hence, our study for the first time highlights the impact of the pharmacological blockade of mTORC2 as a potent novel anti-cancer approach for liver metastasis from melanoma.

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Section: Introductionmentioning

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Pharmacological Inhibition of mTORC2 Reduces Migration and Metastasis in Melanoma

Guenzle

Akasaka

Joechle

et al. 2020

IJMS

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“…Moreover, since aggressive and highly metastatic cutaneous melanoma involves the overexpression of Rictor, the major regulator of Akt phosphorylation, the effect of Rictor inhibition in melanoma models with specific accent on liver metastasis has been investigated. Schmidt et al reported for the first time that mTORC2/Rictor play a critical role in melanoma liver metastasis via the interactions between cancer cells and cancer-associated hepatic stellate cells (HSC); inhibition of mTORC2/Rictor led to significant inhibition of Akt phosphorylation and motility of the cancer cells [119]. Additionally, Damsky et al reported that mTORC1 activation blocked BrafV600E-induced growth arrest but was insufficient for the arrest of melanoma development, concluding that activation of both mTORC1/2 is required for Braf-induced melanomagenesis [120].…”

Section: Cutaneous Cancers Associated With Dysregulation Of the Pimentioning

confidence: 99%

Role and Therapeutic Targeting of the PI3K/Akt/mTOR Signaling Pathway in Skin Cancer: A Review of Current Status and Future Trends on Natural and Synthetic Agents Therapy

Chamcheu

Roy

Uddin

et al. 2019

Cells

134

122

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The mammalian or mechanistic target of rapamycin (mTOR) and associated phosphatidyl-inositiol 3-kinase (PI3K)/protein kinase B (Akt) pathways regulate cell growth, differentiation, migration, and survival, as well as angiogenesis and metabolism. Dysregulation of these pathways is frequently associated with genetic/epigenetic alterations and predicts poor treatment outcomes in a variety of human cancers including cutaneous malignancies like melanoma and non-melanoma skin cancers. Recently, the enhanced understanding of the molecular and genetic basis of skin dysfunction in patients with skin cancers has provided a strong basis for the development of novel therapeutic strategies for these obdurate groups of skin cancers. This review summarizes recent advances in the roles of PI3K/Akt/mTOR and their targets in the development and progression of a broad spectrum of cutaneous cancers and discusses the current progress in preclinical and clinical studies for the development of PI3K/Akt/mTOR targeted therapies with nutraceuticals and synthetic small molecule inhibitors.

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“…We need to investigate whether this splenic injection model can be applied to other types of mice such as HGF knock-in mice. Additionally, the growth of hepatic tumors established by the injection of MUM cells was much slower compared to liver metastasis mouse models using cutaneous melanoma [44,45]. We also notice that our established MUM cell lines generally grow much slower than other cancer cell lines.…”

Section: Evaluation Of Therapeutic Effect On Um Liver Metastasis Usinmentioning

confidence: 74%

Development and optimization of orthotopic liver metastasis xenograft mouse models in uveal melanoma

et al. 2020

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Background: Patients with metastatic uveal melanoma (MUM) in the liver usually die within 1 year. The development of new treatments for MUM has been limited by the lack of diverse MUM cell lines and appropriate animal models. We previously reported that orthotopic xenograft mouse models established by direct injection of MUM cells into the liver were useful for the analysis associated with tumor microenvironment in the liver. However, considering that patients with UM metastasize to the liver hematogenously, direct liver injection model might not be suitable for investigation on various mechanisms of liver metastasis. Here, we aim to establish new orthotopic xenograft models via hematogenous dissemination of tumor cells to the liver, and to compare their characteristics with the hepatic injection model. We also determine if hepatic tumors could be effectively monitored with non-invasive live imaging. Methods: tdtTomate-labeled, patient-derived MUM cells were injected into the liver, spleen or tail vein of immunodeficient NSG mice. Tumor growth was serially assessed with In Vivo Imaging System (IVIS) images once every week. Established hepatic tumors were evaluated with CT scan and then analyzed histologically. Results: We found that splenic injection could consistently establish hepatic tumors. Non-invasive imaging showed that the splenic injection model had more consistent and stronger fluorescent intensity compared to the hepatic injection model. There were no significant differences in tumor growth between splenic injection with splenectomy and without splenectomy. The splenic injection established hepatic tumors diffusely throughout the liver, while the hepatic injection of tumor cells established a single localized tumor. Long-term monitoring of tumor development showed that tumor growth, tumor distribution in the liver, and overall survival depended on the number of tumor cells injected to the spleen. Conclusion: We established a new orthotopic hepatic metastatic xenograft mouse model by splenic injection of MUM cells. The growth of orthotopic hepatic tumors could be monitored with non-invasive IVIS imaging. Moreover, we evaluated the therapeutic effect of a MEK inhibitor by using this model. Our findings suggest that our new orthotopic liver metastatic mouse model may be useful for preclinical drug screening experiments and for the analysis of liver metastasis mechanisms.

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Inhibition of mTORC2/RICTOR Impairs Melanoma Hepatic Metastasis

Cited by 24 publications

References 59 publications

Pharmacological Inhibition of mTORC2 Reduces Migration and Metastasis in Melanoma

Pharmacological Inhibition of mTORC2 Reduces Migration and Metastasis in Melanoma

Role and Therapeutic Targeting of the PI3K/Akt/mTOR Signaling Pathway in Skin Cancer: A Review of Current Status and Future Trends on Natural and Synthetic Agents Therapy

Development and optimization of orthotopic liver metastasis xenograft mouse models in uveal melanoma

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