Drug (ID: DG00045) and It's Reported Resistant Information
Name
Sirolimus
Synonyms
53123-88-9; Rapamune; Rapamycin (Sirolimus); AY-22989; Rapammune; sirolimusum; WY-090217; RAPA; Antibiotic AY 22989; AY 22989; UNII-W36ZG6FT64; CCRIS 9024; CHEBI:9168; SILA 9268A; W36ZG6FT64; HSDB 7284; C51H79NO13; NSC 226080; DE-109; NCGC00021305-05; DSSTox_CID_3582; DSSTox_RID_77091; DSSTox_GSID_23582; Cypher; Supralimus; Wy 090217; Perceiva; RAP; RPM; Rapamycin from Streptomyces hygroscopicus; SIIA 9268A; LCP-Siro; MS-R001; Rapamune (TN); Rapamycin (TN); Sirolimus (RAPAMUNE); Rapamycin C-7, analog 4; Sirolimus (USAN/INN); Sirolimus [USAN:BAN:INN]; Sirolimus, Rapamune,Rapamycin; Heptadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-4-hydroxy; 23,27-Epoxy-3H-pyrido(2,1-c)(1,4)oxaazacyclohentriacontine; 23,27-Epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine; 23,27-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29; 3H-pyrido(2,1-c)(1,4)oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone; Sirolimus (MTOR inhibitor)
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Indication
In total 3 Indication(s)
Multiple myeloma [ICD-11: 2A83]
Approved
[1]
Transplant rejection [ICD-11: NE84]
Approved
[1]
Hydrocephalus [ICD-11: 8D64]
Phase 1/2
[1]
Structure
Drug Resistance Disease(s)
Disease(s) with Clinically Reported Resistance for This Drug (2 diseases)
Breast cancer [ICD-11: 2C60]
[2]
Chordoma [ICD-11: 2B5J]
[3]
Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (2 diseases)
Bladder cancer [ICD-11: 2C94]
[4]
Mature B-cell neoplasms/lymphoma [ICD-11: 2A85]
[5]
Target PI3K/AKT/mTOR pathway (PAm pathway) NOUNIPROTAC [1]
Serine/threonine-protein kinase mTOR (mTOR) MTOR_HUMAN [1]
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Formula
C51H79NO13
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)O)C)/C)O)OC)C)C)/C)OC
InChI
1S/C51H79NO13/c1-30-16-12-11-13-17-31(2)42(61-8)28-38-21-19-36(7)51(60,65-38)48(57)49(58)52-23-15-14-18-39(52)50(59)64-43(33(4)26-37-20-22-40(53)44(27-37)62-9)29-41(54)32(3)25-35(6)46(56)47(63-10)45(55)34(5)24-30/h11-13,16-17,25,30,32-34,36-40,42-44,46-47,53,56,60H,14-15,18-24,26-29H2,1-10H3/b13-11+,16-12+,31-17+,35-25+/t30-,32-,33-,34-,36-,37+,38+,39+,40-,42+,43+,44-,46-,47+,51-/m1/s1
InChIKey
QFJCIRLUMZQUOT-HPLJOQBZSA-N
PubChem CID
5284616
ChEBI ID
CHEBI:9168
TTD Drug ID
D03LJR
VARIDT ID
DR00262
INTEDE ID
DR1489
DrugBank ID
DB00877
Type(s) of Resistant Mechanism of This Drug
  ADTT: Aberration of the Drug's Therapeutic Target
  EADR: Epigenetic Alteration of DNA, RNA or Protein
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Their Corresponding Diseases
ICD-02: Benign/in-situ/malignant neoplasm
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Mature B-cell neoplasms/lymphoma [ICD-11: 2A85]
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: Growth arrest specific 5 (GAS5) [5]
Molecule Alteration Expression
Down-regulation
Resistant Disease Mantle cell lymphoma [ICD-11: 2A85.0]
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell proliferation Activation hsa05200
mTOR signaling pathway Regulation hsa04150
In Vitro Model Z138 cells Peripheral blood Homo sapiens (Human) CVCL_B077
Jeko-1 cells Blood Homo sapiens (Human) CVCL_1865
Experiment for
Molecule Alteration
RT-PCR
Experiment for
Drug Resistance
Nigrosin exclusion analysis
Mechanism Description Small interfering RNAs (sirRNAs) targeting GAS5 protect the cell viability and proliferation of jeko-1 and z-138 cells from the inhibitory effects of mTOR inhibitors result in rapamycin resistance.
Key Molecule: Growth arrest specific 5 (GAS5) [5]
Molecule Alteration Expression
Down-regulation
Resistant Disease Mantle cell lymphoma [ICD-11: 2A85.0]
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell proliferation Activation hsa05200
mTOR signaling pathway Regulation hsa04150
In Vitro Model Z138 cells Peripheral blood Homo sapiens (Human) CVCL_B077
Jeko-1 cells Blood Homo sapiens (Human) CVCL_1865
Experiment for
Molecule Alteration
RT-PCR
Experiment for
Drug Resistance
Nigrosin exclusion analysis
Mechanism Description Small interfering RNAs (sirRNAs) targeting GAS5 protect the cell viability and proliferation of jeko-1 and z-138 cells from the inhibitory effects of mTOR inhibitors result in rapamycin resistance.
Osteosarcoma [ICD-11: 2B51]
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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-410 [1]
Molecule Alteration Expression
Up-regulation
Sensitive Disease Osteosarcoma [ICD-11: 2B51.0]
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HEK293T cells Kidney Homo sapiens (Human) CVCL_0063
MG63 cells Bone marrow Homo sapiens (Human) CVCL_0426
U2OS cells Bone Homo sapiens (Human) CVCL_0042
HFob 1.19 Bone Homo sapiens (Human) CVCL_3708
Experiment for
Molecule Alteration
RT-qPCR
Experiment for
Drug Resistance
MTT assay
Mechanism Description microRNA-410 regulates autophagy-related gene ATG16L1 expression and enhances chemosensitivity via autophagy inhibition in osteosarcoma, miR410 directly decreased ATG16L1 expression by targeting its 3'-untranslated region.
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Autophagy-related protein 16-1 (ATG16L1) [1]
Molecule Alteration Expression
Down-regulation
Sensitive Disease Osteosarcoma [ICD-11: 2B51.0]
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HEK293T cells Kidney Homo sapiens (Human) CVCL_0063
MG63 cells Bone marrow Homo sapiens (Human) CVCL_0426
U2OS cells Bone Homo sapiens (Human) CVCL_0042
HFob 1.19 Bone Homo sapiens (Human) CVCL_3708
Experiment for
Molecule Alteration
Luciferase reporter assay; Western blot analysis
Experiment for
Drug Resistance
MTT assay
Mechanism Description microRNA-410 regulates autophagy-related gene ATG16L1 expression and enhances chemosensitivity via autophagy inhibition in osteosarcoma, miR410 directly decreased ATG16L1 expression by targeting its 3'-untranslated region.
Chordoma [ICD-11: 2B5J]
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Y-box-binding protein 1 (YBX1) [3]
Molecule Alteration Expression
Up-regulation
Resistant Disease Chordoma [ICD-11: 2B5J.0]
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation EGFR/AKT signaling pathway Regulation hsa04012
Cell invasion Activation hsa05200
In Vitro Model Chordoma tissue N.A.
In Vivo Model NOD/SCID/IL2Rgamma null (NOG) mouse xenograft model Mus musculus
Experiment for
Molecule Alteration
Western blotting analysis
Experiment for
Drug Resistance
CCK-8 assay
Mechanism Description YBX1 regulated protein expression of pEGFR, pAKT and its downstream target genes that influenced cell apoptosis, cell cycle transition and cell invasion. YBX1 activated the EGFR/AKT pathway in chordoma and YBX1-induced elevated expression of key molecules in the EGFR/AKT pathway were downregulated by EGFR and AKT pathway inhibitors. These in vitro results were further confirmed by in vivo data. These data showed that YBX1 promoted tumorigenesis and progression in spinal chordoma via the EGFR/AKT pathway. YBX1 might serve as a prognostic and predictive biomarker, as well as a rational therapeutic target, for chordoma.
Breast cancer [ICD-11: 2C60]
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase mTOR (mTOR) [2]
Molecule Alteration Missense mutation
p.F2108L
Resistant Disease Breast cancer [ICD-11: 2C60.3]
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation PIk3CA/AKT/mTOR signaling pathway Activation hsa04211
In Vitro Model MCF-7 cells Breast Homo sapiens (Human) CVCL_0031
MDA-MB-468 cells Breast Homo sapiens (Human) CVCL_0419
Experiment for
Molecule Alteration
Integrated Mutation Profiling of Actionable Cancer Targets assay; Sanger sequencing assay
Experiment for
Drug Resistance
CellTiter-Glo luminescent cell viability assay
Mechanism Description The clinical relevance of these mutations is supported by a case report of a patient who acquired the identical F2108L mTOR mutation after relapse under everolimus treatment.
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Ubiquitin protein ligase E3 component n-recognin 5 (UBR5) [6]
Molecule Alteration Expression
Up-regulation
Resistant Disease Breast cancer [ICD-11: 2C60.3]
Experimental Note Identified from the Human Clinical Data
In Vitro Model MCF-7 cells Breast Homo sapiens (Human) CVCL_0031
MDA-MB-436 cells Breast Homo sapiens (Human) CVCL_0623
Experiment for
Molecule Alteration
Western blotting analysis
Experiment for
Drug Resistance
MTS assay
Mechanism Description High nuclear EDD expression in a cohort of 151 women with serous ovarian carcinoma was associated with an increased risk of disease recurrence following first-line chemotherapy, and siRNA-knockdown of EDD gene expression partially restored cisplatin sensitivity in cisplatin-resistant ovarian cancer cells in vitro. Loss of EDD induced cell-cycle arrest at G1 through upregulation of tumour suppressor p53 and p21 proteins in osteosarcoma cells in vitro.
Cervical cancer [ICD-11: 2C77]
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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-218 [7]
Molecule Alteration Expression
Up-regulation
Sensitive Disease Cervical cancer [ICD-11: 2C77.0]
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
mTOR signaling pathway Inhibition hsa04150
In Vitro Model Hela cells Cervix uteri Homo sapiens (Human) CVCL_0030
Siha cells Cervix uteri Homo sapiens (Human) CVCL_0032
Caski cells Uterus Homo sapiens (Human) CVCL_1100
C33A cells Uterus Homo sapiens (Human) CVCL_1094
In Vivo Model Mouse bearing cervical cancer model Mus musculus
Experiment for
Molecule Alteration
RT-PCR
Experiment for
Drug Resistance
MTT assay; Flow cytometry assay
Mechanism Description microRNA-218 increases cellular sensitivity to Rapamycin via targeting Rictor and reducing the level of Rictor in cervical cancer.
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Rapamycin-insensitive companion of mTOR (RICTOR) [7]
Molecule Alteration Expression
Down-regulation
Sensitive Disease Cervical cancer [ICD-11: 2C77.0]
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
mTOR signaling pathway Inhibition hsa04150
In Vitro Model Hela cells Cervix uteri Homo sapiens (Human) CVCL_0030
Siha cells Cervix uteri Homo sapiens (Human) CVCL_0032
Caski cells Uterus Homo sapiens (Human) CVCL_1100
C33A cells Uterus Homo sapiens (Human) CVCL_1094
In Vivo Model Mouse bearing cervical cancer model Mus musculus
Experiment for
Molecule Alteration
RT-qPCR
Experiment for
Drug Resistance
MTT assay; Flow cytometry assay
Mechanism Description microRNA-218 increases cellular sensitivity to Rapamycin via targeting Rictor and reducing the level of Rictor in cervical cancer.
Prostate cancer [ICD-11: 2C82]
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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: Growth arrest specific 5 (GAS5) [8]
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
LNCaP cells Prostate Homo sapiens (Human) CVCL_0395
PC3 cells Prostate Homo sapiens (Human) CVCL_0035
22RV1 cells Prostate Homo sapiens (Human) CVCL_1045
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.
Bladder cancer [ICD-11: 2C94]
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-miR-582-5p [4]
Molecule Alteration Expression
Up-regulation
Resistant Disease Bladder cancer [ICD-11: 2C94.0]
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell viability Activation hsa05200
In Vitro Model 5637 cells Bladder Homo sapiens (Human) CVCL_0126
EJ cells Bladder Homo sapiens (Human) CVCL_UI82
J82 cells Bladder Homo sapiens (Human) CVCL_0359
SV-HUC-1 cells Bladder Homo sapiens (Human) CVCL_3798
T24 cells Bladder Homo sapiens (Human) CVCL_0554
HT1376 cells Bladder Homo sapiens (Human) CVCL_1292
In Vivo Model BALB/c nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration
qRT-PCR
Experiment for
Drug Resistance
CCK8 assay
Mechanism Description UCA1 knockdown suppresses growth, migration, and invasion of T24 and 5637 cells via derepression of miR-582-5p and ATG7 was downregulated by UCA1 shRNA and upregulated by miR-582-5p inhibitor.
Key Molecule: Urothelial cancer associated 1 (UCA1) [4]
Molecule Alteration Expression
Down-regulation
Resistant Disease Bladder cancer [ICD-11: 2C94.0]
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell viability Activation hsa05200
In Vitro Model 5637 cells Bladder Homo sapiens (Human) CVCL_0126
EJ cells Bladder Homo sapiens (Human) CVCL_UI82
J82 cells Bladder Homo sapiens (Human) CVCL_0359
SV-HUC-1 cells Bladder Homo sapiens (Human) CVCL_3798
T24 cells Bladder Homo sapiens (Human) CVCL_0554
HT1376 cells Bladder Homo sapiens (Human) CVCL_1292
In Vivo Model BALB/c nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration
qRT-PCR
Experiment for
Drug Resistance
CCK8 assay
Mechanism Description UCA1 knockdown suppresses growth, migration, and invasion of T24 and 5637 cells via derepression of miR-582-5p and ATG7 was downregulated by UCA1 shRNA and upregulated by miR-582-5p inhibitor.
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Ubiquitin-like modifier-activating enzyme ATG7 (ATG7) [4]
Molecule Alteration Expression
Down-regulation
Resistant Disease Bladder cancer [ICD-11: 2C94.0]
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell viability Activation hsa05200
In Vitro Model 5637 cells Bladder Homo sapiens (Human) CVCL_0126
EJ cells Bladder Homo sapiens (Human) CVCL_UI82
J82 cells Bladder Homo sapiens (Human) CVCL_0359
SV-HUC-1 cells Bladder Homo sapiens (Human) CVCL_3798
T24 cells Bladder Homo sapiens (Human) CVCL_0554
HT1376 cells Bladder Homo sapiens (Human) CVCL_1292
In Vivo Model BALB/c nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration
Western blot analysis
Experiment for
Drug Resistance
CCK8 assay
Mechanism Description UCA1 knockdown suppresses growth, migration, and invasion of T24 and 5637 cells via derepression of miR-582-5p and ATG7 was downregulated by UCA1 shRNA and upregulated by miR-582-5p inhibitor.
References
Ref 1 MicroRNA-410 regulates autophagy-related gene ATG16L1 expression and enhances chemosensitivity via autophagy inhibition in osteosarcoma. Mol Med Rep. 2017 Mar;15(3):1326-1334. doi: 10.3892/mmr.2017.6149. Epub 2017 Jan 26.
Ref 2 Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor. Nature. 2016 Jun 9;534(7606):272-6. doi: 10.1038/nature17963. Epub 2016 May 18.
Ref 3 Y-box binding protein-1 promotes tumorigenesis and progression via the epidermal growth factor receptor/AKT pathway in spinal chordoma .Cancer Sci. 2019 Jan;110(1):166-179. doi: 10.1111/cas.13875. Epub 2018 Dec 19. 10.1111/cas.13875
Ref 4 Long noncoding RNA UCA1 targets miR-582-5p and contributes to the progression and drug resistance of bladder cancer cells through ATG7-mediated autophagy inhibition. Onco Targets Ther. 2019 Jan 9;12:495-508. doi: 10.2147/OTT.S183940. eCollection 2019.
Ref 5 Role of GAS5 noncoding RNA in mediating the effects of rapamycin and its analogues on mantle cell lymphoma cells. Clin Lymphoma Myeloma Leuk. 2014 Dec;14(6):468-73. doi: 10.1016/j.clml.2014.02.011. Epub 2014 Mar 3.
Ref 6 Prolactin-inducible EDD E3 ubiquitin ligase promotes TORC1 signalling, anti-apoptotic protein expression, and drug resistance in breast cancer cells .Am J Cancer Res. 2019 Jul 1;9(7):1484-1503. eCollection 2019.
Ref 7 MicroRNA-218 increases cellular sensitivity to Rapamycin via targeting Rictor in cervical cancer. APMIS. 2015 Jul;123(7):562-70. doi: 10.1111/apm.12387. Epub 2015 Apr 24.
Ref 8 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.

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