Emerging strategies to overcome the resistance to current mTOR inhibitors in renal cell carcinoma

Santoni, Matteo; Pantano, Francesco; Amantini, Consuelo; Nabissi, Massimo; Conti, Alessandro; Burattini, Luciano; Zoccoli, Alice; Berardi, Rossana; Santoni, Giorgio; Tonini, Giuseppe; Santini, Daniele; Cascinu, Stefano

doi:10.1016/j.bbcan.2014.01.007

Cited by 49 publications

(53 citation statements)

References 117 publications

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“…Several mechanisms by which this occurs have been described, including inhibition of mTORC1 reducing S6‐mediated phosphorylation of RICTOR, a functional repressor of mTORC2, and consequent mTORC2‐mediated activation of pAKT (Santoni et al ., 2014). These findings suggested that by inhibiting the feedback‐mediated activation of pAKT, sensitivity to everolimus may be enhanced.…”

Section: Discussionmentioning

confidence: 99%

“…This was confirmed by the demonstration that dual treatment with everolimus and the pAKT inhibitor, MK2206, resulted in greater inhibition of downstream signalling and cell proliferation. In addition, while dual targeting of mTOR1 and AKT represents one approach of circumventing feedback‐induced pAKT activation, agents that directly inhibit the kinase activity of both mTORC1 and mTORC2 are also being developed, with several agents in early‐phase clinical testing (Santoni et al ., 2014; Schenone et al ., 2011). Indeed, treatment of everolimus‐sensitive BTC cell lines with the ATP‐competitive TORC1/TORC2 inhibitor KU‐0063794 (Garcia‐Martinez et al ., 2009) resulted in robust inhibition of downstream signalling without paradoxical activation of pAKT.…”

Section: Discussionmentioning

confidence: 99%

“…mTORC1 therefore is a major regulator of ribosome biogenesis and protein synthesis, through which it functions to drive cell growth. PI3K/AKT/mTOR signalling is also regulated by multiple negative feedback loops (Beauchamp and Platanias, 2013; Santoni et al ., 2014). For example, S6K inhibits IRS‐1 at both the transcriptional and protein level.…”

Section: Introductionmentioning

confidence: 99%

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K‐Ras mutation and amplification status is predictive of resistance and high basal pAKT is predictive of sensitivity to everolimus in biliary tract cancer cell lines

et al. 2017

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Advanced biliary tract cancer (BTC) has a poor prognosis and limited treatment options. The PI3K/Akt/mTOR signalling pathway is hyperactivated in a subset of BTCs, and clinical activity of the mTOR inhibitor everolimus has been observed in some patients with BTC. The goal of this study was to identify biomarkers predictive of everolimus response. Twenty BTC cell lines were assessed for everolimus sensitivity with a spectrum of growth inhibitory responses observed. Molecular biomarkers of sensitivity and resistance were identified by interrogation of the activation status of the Ras/MAPK and PI3K/Akt/mTOR pathways. K‐Ras mutations and/or amplifications were identified in 45% of cell lines and were associated with resistance to everolimus. Activating mutations in PIK3CA or loss of PTEN was not predictive of everolimus response; however, high basal levels of pAKT were associated with sensitivity, independent of Ras/MAPK pathway activation status. Notably, everolimus inhibited mTOR signalling to a similar extent in sensitive and resistant cell lines, suggesting that relative dependence on the mTOR pathway rather than the magnitude of pathway inhibition determines everolimus response. Consistent with the known limitations of rapalogs, everolimus induced feedback‐mediated activation of AKT in BTC cell lines, which could be overcome by cotreatment with an AKT inhibitor or ATP‐competitive mTORC1/mTORC2 inhibitors. However, both approaches failed to induce greater apoptosis compared to everolimus, and mTORC1/mTORC2 kinase inhibitors induced compensatory activation of pERK, identifying an inherent limitation of these agents in BTC cell lines. These findings suggest that future trials of everolimus in BTC would benefit from preselecting patients based on their K‐Ras and PI3K/mTOR pathway activation status. The study also identifies strategies for enhancing inhibition of the PI3K/mTOR pathway in BTC cell lines.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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K‐Ras mutation and amplification status is predictive of resistance and high basal pAKT is predictive of sensitivity to everolimus in biliary tract cancer cell lines

et al. 2017

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“…These agents have improved clinical outcomes, but drug resistance continues to be a major problem highlighting the need for novel therapeutic strategies (9,10). mTOR is a key regulator of protein synthesis that effects many cellular functions, including cell division, angiogenesis, and apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Targeting Survivin Inhibits Renal Cell Carcinoma Progression and Enhances the Activity of Temsirolimus

Carew

Espitia

Zhao

et al. 2015

Molecular Cancer Therapeutics

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Elevated expression of the antiapoptotic factor survivin has been implicated in cancer cell survival and disease progression. However, its specific contribution to renal cell carcinoma (RCC) pathogenesis is not well defined. We investigated the roles of survivin in RCC tumor progression, resistance to mTOR inhibitors, and evaluated the therapeutic activity of the survivin suppressant YM155 in RCC models. Here, we report that survivin expression levels were significantly higher in RCC cell lines compared with normal renal cells. Stable targeted knockdown of survivin completely abrogated the ability of 786-O RCC tumors to grow in mice, thus demonstrating its importance as a regulator of RCC tumorigenesis. We next explored multiple strategies to therapeutically inhibit survivin function in RCC. Treatment with the mTOR inhibitor temsirolimus partially diminished survivin levels and this effect was augmented by the addition of YM155. Further analyses revealed that, in accordance with their combined anti-survivin effects, YM155 significantly improved the anticancer activity of temsirolimus in a panel of RCC cell lines in vitro and in xenograft models in vivo. Similar to pharmacologic inhibition of survivin, shRNA-mediated silencing of survivin expression not only inhibited RCC tumor growth, but also significantly sensitized RCC cells to temsirolimus therapy. Subsequent experiments demonstrated that the effectiveness of this dual survivin/mTOR inhibition strategy was mediated by a potent decrease in survivin levels and corresponding induction of apoptosis. Our findings establish survivin inhibition as a novel approach to improve RCC therapy that warrants further investigation.

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“…Although its molecular pathophysiology is not completely understood, an improved understanding of the molecular pathogenesis of RCC, particularly in genomics, proteomics and metabolomics, has attracted increasing attention during the last decade (17). These previous studies have allowed for the development of novel therapeutics that target the VEGF and mTOR pathways (18).…”

Section: Discussionmentioning

confidence: 99%

Effects of the novel heat shock protein 90 inhibitor AUY922 in renal cell carcinoma ACHN and 786-O cells

Zhu

et al. 2015

Oncology Letters

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Abstract. The aim of the present study was to investigate the effects of the heat shock protein (HSP)90 inhibitor AUY922 on the proliferation and migratory ability of renal cell carcinoma (RCC) cells. The expression of HSP90 was measured in vitro using western blotting and quantitative polymerase chain reaction in the ACHN and 786-O cell RCC lines, and also in the immortalized normal human proximal tubule epithelium HK-2 cell line. The effects of the time and concentration of AUY922 administration were investigated in the ACHN and 786-O cells, and the cell proliferation was measured using an MTT assay. A Transwell assay was performed to evaluate the migratory ability of ACHN cells following treatment with AUY922 at concentrations of 10, 50 and 100 nM. Western blot analysis and reverse transcription polymerase chain reaction revealed that HSP90 mRNA and protein were overexpressed in the two RCC cell lines compared with the HK-2 cell line. AUY922 inhibited the proliferation of the ACHN and 786-O cells in a time-and concentration-dependent manner, and the migratory ability of the ACHN cells was markedly suppressed subsequent to treatment with AUY922. The present data suggest that the pathogenesis of human RCC may be mediated by HSP90. It was also indicated that the specific HSP90 inhibitor AUY922 plays a therapeutic role in the treatment of RCC, and therefore, HSP90 may be a selective target for molecular-targeted treatments of RCC.

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Emerging strategies to overcome the resistance to current mTOR inhibitors in renal cell carcinoma

Cited by 49 publications

References 117 publications

K‐Ras mutation and amplification status is predictive of resistance and high basal pAKT is predictive of sensitivity to everolimus in biliary tract cancer cell lines

K‐Ras mutation and amplification status is predictive of resistance and high basal pAKT is predictive of sensitivity to everolimus in biliary tract cancer cell lines

Targeting Survivin Inhibits Renal Cell Carcinoma Progression and Enhances the Activity of Temsirolimus

Effects of the novel heat shock protein 90 inhibitor AUY922 in renal cell carcinoma ACHN and 786-O cells

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