Drug Information

Drug (ID: DG00208) and It's Reported Resistant Information

• Name: Everolimus
• Synonyms: Afinitor; Afinitor (TN); CERTICAN(R); Certican; Certican (TN); Everolimus (JAN/USAN/INN); Everolimus [USAN]; MTOR kinase inhibitors; NVP-RAD-001; RAD 001; RAD-001; RAD-001C; RAD001; RAD001, SDZ-RAD, Certican, Zortress, Afinitor, Everolimus; SDZ-RAD; Zortress
• Indication:
  In total 1 Indication(s)
  Renal cell carcinoma [ICD-11: 2C90]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (5 diseases)
  Breast cancer [ICD-11: 2C60]; [2]
  Kidney cancer [ICD-11: 2C90]; [3]
  Pancreatic cancer [ICD-11: 2C10]; [4]
  Prostate hyperplasia [ICD-11: GA90]; [5]
  Thyroid cancer [ICD-11: 2D10]; [6]
• Target: Serine/threonine-protein kinase mTOR (mTOR); MTOR_HUMAN; [1]
• Formula: C53H83NO14
• IsoSMILES: C[C@@H]1CC[C@H]2C[C@@H](/C(=C/C=C/C=C/[C@H](C[C@H](C(=O)[C@@H]([C@@H](/C(=C/[C@H](C(=O)C[C@H](OC(=O)[C@@H]3CCCCN3C(=O)C(=O)[C@@]1(O2)O)[C@H](C)C[C@@H]4CC[C@H]([C@@H](C4)OC)OCCO)C)/C)O)OC)C)C)/C)OC
• InChI: 1S/C53H83NO14/c1-32-16-12-11-13-17-33(2)44(63-8)30-40-21-19-38(7)53(62,68-40)50(59)51(60)54-23-15-14-18-41(54)52(61)67-45(35(4)28-39-20-22-43(66-25-24-55)46(29-39)64-9)31-42(56)34(3)27-37(6)48(58)49(65-10)47(57)36(5)26-32/h11-13,16-17,27,32,34-36,38-41,43-46,48-49,55,58,62H,14-15,18-26,28-31H2,1-10H3/b13-11+,16-12+,33-17+,37-27+/t32-,34-,35-,36-,38-,39+,40+,41+,43-,44+,45+,46-,48-,49+,53-/m1/s1
• InChIKey: HKVAMNSJSFKALM-GKUWKFKPSA-N
• PubChem CID: 6442177
• ChEBI ID: CHEBI:68478
• TTD Drug ID: D0K3QS
• VARIDT ID: DR00224
• INTEDE ID: DR0674
• DrugBank ID: DB01590

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  RTDM: Regulation by the Disease Microenvironment

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Pancreatic cancer [ICD-11: 2C10]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Eukaryotic translation initiation factor 4E binding protein 1 (EIF4EBP1) [4]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Pancreatic neuroendocrine tumor [ICD-11: 2C10.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K/AKT/mTOR signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: CXCR4-CXCL12-CXCR7 signaling pathway; Activation; hsa04061
• In Vitro Model: A498 cells; Kidney; Homo sapiens (Human); CVCL_1056
• In Vitro Model: SN12C cells; Kidney; Homo sapiens (Human); CVCL_1705
• Experiment for Molecule Alteration: Western blotting assay
• Mechanism Description: When the CXCR4-CXCL12-CXCR7 pathway is activated through CXCL12 in human renal cancer cells were, SN12C and A498, CXCL12 induced the mTOR targets p-P70S6K and p-4EBP1.The combination therapy of mTOR inhibitors with the CXCR4-CXCL12-CXCR7 axis inhibitors in renal cancer tumors could overcome the Everolimus resistance.

Key Molecule: Ribosomal protein S6 kinase beta-1 (RPS6KB1) [4]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Pancreatic neuroendocrine tumor [ICD-11: 2C10.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K/AKT/mTOR signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: CXCR4-CXCL12-CXCR7 signaling pathway; Activation; hsa04061
• In Vitro Model: A498 cells; Kidney; Homo sapiens (Human); CVCL_1056
• In Vitro Model: SN12C cells; Kidney; Homo sapiens (Human); CVCL_1705
• Experiment for Molecule Alteration: Western blotting assay
• Mechanism Description: When the CXCR4-CXCL12-CXCR7 pathway is activated through CXCL12 in human renal cancer cells were, SN12C and A498, CXCL12 induced the mTOR targets p-P70S6K and p-4EBP1.The combination therapy of mTOR inhibitors with the CXCR4-CXCL12-CXCR7 axis inhibitors in renal cancer tumors could overcome the Everolimus resistance.

Breast cancer [ICD-11: 2C60]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Mth938 domain-containing protein (AAMDC) [2]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/AKT/mTOR signaling pathway; Activation; hsa04151
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: SkBR3 cells; Breast; Homo sapiens (Human); CVCL_0033
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: ZR75-1 cells; Breast; Homo sapiens (Human); CVCL_0588
• In Vitro Model: BT549 cells; Breast; Homo sapiens (Human); CVCL_1092
• In Vitro Model: MCF-12A cells; Breast; Homo sapiens (Human); CVCL_3744
• In Vitro Model: SUM159 cells; Breast; Homo sapiens (Human); CVCL_5423
• In Vitro Model: SUM44PE cells; Breast; Homo sapiens (Human); CVCL_3424
• In Vitro Model: SUM52PE cells; Breast; Homo sapiens (Human); CVCL_3425
• In Vivo Model: BALB/cJ Foxn1/Arc nude mice xenografts model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo 2.0 luminescence assay protocol assay
• Mechanism Description: High AAMDC expression is associated with sensitization to dactolisib and everolimus, and these PI3k-mTOR inhibitors exhibit synergistic interactions with anti-estrogens in IntClust2 models. Ectopic AAMDC expression is sufficient to activate AkT signaling, resulting in estrogen-independent tumor growth. Thus, AAMDC-overexpressing tumors may be sensitive to PI3k-mTORC1 blockers in combination with anti-estrogens.

Prostate cancer [ICD-11: 2C82]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Growth arrest specific 5 (GAS5) [1]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: 22RV1 cells; Prostate; Homo sapiens (Human); CVCL_1045
• In Vitro Model: PNT2C2 cells; Prostate; Homo sapiens (Human); CVCL_4889
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: GAS5 assay; MTS assay
• Mechanism Description: First generation mTORC1, combined mTORC1/mTORC2 and dual PI3k/mTOR inhibitors all increased cellular GAS5 levels and inhibited culture growth in androgen-dependent (LNCaP) and androgen-sensitive (22Rv1) cell lines, but not in androgen-independent (PC-3 and DU 145) cell lines. The latter exhibited low endogenous GAS5 expression, and GAS5 silencing in LNCaP and 22Rv1 cells decreased the sensitivity to mTOR inhibitors, whereas transfection of GAS5 LncRNA sensitized PC-3 and DU 145 cells to these agents.

Kidney cancer [ICD-11: 2C90]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: hsa-mir-92a [3]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Kidney cancer [ICD-11: 2C90.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Caki-1 cells; Kidney; Homo sapiens (Human); CVCL_0234
• In Vitro Model: 786-O cells; Kidney; Homo sapiens (Human); CVCL_1051
• In Vitro Model: ACHN cells; Pleural effusion; Homo sapiens (Human); CVCL_1067
• In Vitro Model: A498 cells; Kidney; Homo sapiens (Human); CVCL_1056
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: NC886 also promotes renal cancer cell drug-resistance to Sunitinib or Everolimus by promoting EMT through Rock2 phosphorylation-mediated nuclear translocation of beta-catenin.

Thyroid cancer [ICD-11: 2D10]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine/threonine-protein kinase mTOR (mTOR) [6]

• Molecule Alteration: Missense mutation; p.F2108L
• Resistant Disease: Thyroid carcinoma [ICD-11: 2D10.4]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: mTOR signaling pathway; Activation; hsa04150
• Experiment for Molecule Alteration: Whole-exome sequencing assay; Whole-genome sequencing assay
• Experiment for Drug Resistance: Computerized tomography assay
• Mechanism Description: On the basis of these findings, we hypothesized that mTORF2108L causes resistance to allosteric mTOR inhibition by preventing the binding of the drug to the protein.

ICD-16: Genitourinary system diseases

Prostate hyperplasia [ICD-11: GA90]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: NPR2 like, GATOR1 complex subunit (NPRL2) [5]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Prostate hyperplasia [ICD-11: GA90.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: mTOR signaling pathway; Inhibition; hsa04150
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: RWPE-1 cells; Prostate; Homo sapiens (Human); CVCL_3791
• In Vitro Model: PCa LNCaP cells; Prostate; Homo sapiens (Human); CVCL_D575
• In Vivo Model: Balb/c athymic nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: NPRL2 enhances autophagy and the resistance to Everolimus in castration-resistant prostate cancer.NPRL2-silencing increased the activity of mTOR signaling, and the autophagy attenuation induced by NPRL2-silencing in EVS-treated CRPC cells was associated with the increase of apoptosis.

References

• Ref 1: Reciprocal regulation of GAS5 lncRNA levels and mTOR inhibitor action in prostate cancer cells. Prostate. 2015 May;75(7):693-705. doi: 10.1002/pros.22952. Epub 2015 Feb 3.
• Ref 2: The oncogene AAMDC links PI3K-AKT-mTOR signaling with metabolic reprograming in estrogen receptor-positive breast cancer. Nat Commun. 2021 Mar 26;12(1):1920. doi: 10.1038/s41467-021-22101-7.
• Ref 3: Nc886 promotes renal cancer cell drug-resistance by enhancing EMT through Rock2 phosphorylation-mediated Beta-catenin nuclear translocation .Cell Cycle. 2022 Feb;21(4):340-351. doi: 10.1080/15384101.2021.2020431. Epub 2022 Jan 2. 10.1080/15384101.2021.2020431
• Ref 4: Everolimus and pancreatic neuroendocrine tumors (PNETs): Activity, resistance and how to overcome it .Int J Surg. 2015 Sep;21 Suppl 1:S89-94. doi: 10.1016/j.ijsu.2015.06.064. Epub 2015 Jun 27. 10.1016/j.ijsu.2015.06.064
• Ref 5: NPRL2 enhances autophagy and the resistance to Everolimus in castration-resistant prostate cancer .Prostate. 2019 Jan;79(1):44-53. doi: 10.1002/pros.23709. Epub 2018 Sep 3. 10.1002/pros.23709
• Ref 6: Response and acquired resistance to everolimus in anaplastic thyroid cancer. N Engl J Med. 2014 Oct 9;371(15):1426-33. doi: 10.1056/NEJMoa1403352.