Mechanistic Target of Rapamycin Inhibitors in Renal Cell Carcinoma: Potential, Limitations, and Perspectives

Faes, Seraina; Demartines, Nicolas; Dormond, Olivier

doi:10.3389/fcell.2021.636037

Cited by 27 publications

(21 citation statements)

References 83 publications

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“…Nowadays, our efforts have largely improved the management of ccRCC patients. Apart from surgical resection, molecular targeted drugs, including drugs targeting VEGF, PDGFR, EGFR, and mTOR, are available for patients with high recurrence risk and for patients lacking opportunity for radical resection [47,48]. However, the therapeutic effects are still not very satisfying and there is no doubt that ccRCC is a In this study, we are mainly focused on IL20RB, whose role in ccRCC is still unknown but has shown its potential as a novel biomarker in some human cancers.…”

Section: Discussionmentioning

confidence: 99%

Identification of IL20RB as a Novel Prognostic and Therapeutic Biomarker in Clear Cell Renal Cell Carcinoma

et al. 2022

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Background. Clear cell renal cell carcinoma (ccRCC) is a type of life-threatening malignant tumor of the urinary system. IL20RB, interleukin 20 receptor subunit beta, is a cytokine receptor subunit coding gene and was initially found to play a vital role in human cancers, while its role in ccRCC still remains unclear. Methods. In this work, we explored the prognostic value and therapeutic potential of IL20RB in ccRCC mainly by online tools. Firstly, we used UALCAN and GEPIA to explore the expression profile and prognostic value of IL20RB in various cancers; the expression profile in tumor cell lines was also analysed with CCLE and Expression Atlas. Then, we decided to focus on ccRCC for further analysis; we further demonstrated the significant correlation between expression and clinical features by GEPIA and UALCAN. In order to reveal the potential intrinsic mechanism responsible for the upregulation of IL20RB in ccRCC, we made genetic alternation analysis and methylation analysis. cBioPortal was used for genetic alternation analysis. UALCAN, MethSurv, and Xena were used for methylation analysis. To learn details of how IL20RB might function in ccRCC, we further conducted functional analysis and immune infiltration analysis. STRING and GSEA were used to do functional analysis. TIMER was used for immune infiltration analysis; KM plotter was used for survival analysis. Results. Results show that IL20RB is upregulated in ccRCC, and low methylation may be responsible for its upregulation. Both high expression and low methylation of IL20RB predict worse survival, and both have a strong positive correlation with clinical characteristics. In addition, results indicate that there exists a crosstalk between IL20RB and neutrophils. Furthermore, the immune microenvironment could influence the prognosis predicting ability of IL20RB. Conclusions. In conclusion, IL20RB plays an important role in ccRCC and is identified as a novel prognostic and potential therapeutic biomarker in ccRCC.

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Section: Discussionmentioning

confidence: 99%

Identification of IL20RB as a Novel Prognostic and Therapeutic Biomarker in Clear Cell Renal Cell Carcinoma

et al. 2022

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“…MTOR activation occurs frequently in cancers and targeting MTOR using RAD001 has been extensively tested in clinical trials, revealing RAD001 is safe, tolerable and has efficacy at blocking tumor growth in patients (44).…”

Section: Discussionmentioning

confidence: 99%

“…Here, we showed the FDA-approved MTOR inhibitor, RAD001, could be used to block MDR1 activity overcoming MDR1-mediated drug resistance in cancer cells. MTOR activation occurs frequently in cancers and targeting MTOR using RAD001 has been extensively tested in clinical trials, revealing RAD001 is safe, tolerable and has efficacy at blocking tumor growth in patients ( 44 ). RAD001 is currently used to treat several cancers, including renal cell carcinomas (RCC) (NCT00831480), which exhibits frequent overexpression of MDR1 ( 45 ).…”

Section: Discussionmentioning

confidence: 99%

MDR1 Drug Efflux Pump Promotes Intrinsic and Acquired Resistance to PROTACs in Cancer Cells

Kurimchak

Herrera-Montávez

Montserrat‐Sangrà

et al. 2021

Preprint

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PROTACs (Proteolysis-Targeting Chimeras) represent a promising new class of drugs that selectively degrade proteins of interest from cells. PROTACs targeting oncogenes are avidly being explored for cancer therapies, with several currently in clinical trials. Drug resistance represents a significant challenge in cancer therapies, and the mechanism by which cancer cells acquire resistance to PROTACs remains poorly understood. Using proteomics, we discovered acquired and intrinsic resistance to PROTACs in cancer cells can be mediated by upregulation of the drug efflux pump MDR1. PROTAC-resistant cells could be re-sensitized to PROTACs through co-administering MDR1 inhibitors. Notably, co-treatment of MDR1-overexpressing colorectal cancer cells with MEK1/2 or KRASG12C degraders and the dual ErbB receptor/MDR1 inhibitor lapatinib exhibited potent drug synergy due to simultaneous blockade of MDR1 and ErbB receptor activity. Together, our findings suggest that concurrent blockade of MDR1 will likely be required in combination with PROTACs to achieve durable protein degradation and therapeutic response in cancer.

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“…Furthermore, the immunosuppressant effect of rapamycin has been observed in several case studies, with transplanted patients reducing the incidence of cancer [118]. In ongoing clinical studies in prostate cancer in which the PI3K/Akt/mTOR pathway is highly expressed, it was observed that rapamycin and its derivatives were well tolerated in prostate cancer patients and decreased mTOR level [119]. In addition to the antiproliferative effect, RAD001 is also used as an immunosuppressant for the treatment of several malignancies in phase I study [120].…”

Section: Phosphoinositide 3-kinase (Pi3k) Pathway Inhibitorsmentioning

confidence: 98%

The Role of Kinase Inhibitors in Cancer Therapies

Kursunluoglu¹,

Erdogan²,

Cagatay³

et al. 2021

Protein Kinases - Promising Targets for Anticancer Drug Research

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Protein kinases are enzymes that transfer a phosphate group to the threonine, serine, or tyrosine residues of the target protein, regulating its activity. The activity of these enzymes are very important and strictly regulated in the cell as they promote cell proliferation, survival, and migration. In the case of any dysregulation of these enzymes, they can be associated with cancer initiation and progression. Small-molecule kinase inhibitors approved by the FDA for their improved clinical benefits are currently used in targeted therapy for the treatment of various cancers. So far, there are 62 FDA-approved therapeutic agents targeting different protein kinases, eight of which were approved in 2020. Today, kinase inhibitors are used as FDA approved cancer agents and newly developed ones are evaluated in clinical trials. Those protein kinase inhibitors can be grouped as growth factor receptor inhibitors, Ras/Raf/Mek inhibitors, phosphoinositide 3-kinase (PI3K) and cyclin dependent kinase inhibitors, other targets, and agents such as protein kinase c and 3 phosphoinositide-dependent kinase 1. In this chapter, these kinases, their pathways, and their inhibitors will be discussed in detail.

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Mechanistic Target of Rapamycin Inhibitors in Renal Cell Carcinoma: Potential, Limitations, and Perspectives

Cited by 27 publications

References 83 publications

Identification of IL20RB as a Novel Prognostic and Therapeutic Biomarker in Clear Cell Renal Cell Carcinoma

Identification of IL20RB as a Novel Prognostic and Therapeutic Biomarker in Clear Cell Renal Cell Carcinoma

MDR1 Drug Efflux Pump Promotes Intrinsic and Acquired Resistance to PROTACs in Cancer Cells

The Role of Kinase Inhibitors in Cancer Therapies

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