Molecule Information

General Information of the Molecule (ID: Mol00701)

• Name: Wee1-like protein kinase (WEE1) ,Homo sapiens
• Synonyms: WEE1hu; Wee1A kinase
• Molecule Type: Protein
• Gene Name: WEE1
• Gene ID: 7465
• Location: chr11:9573670-9593457[+]
• Sequence:
  MSFLSRQQPPPPRRAGAACTLRQKLIFSPCSDCEEEEEEEEEEGSGHSTGEDSAFQEPDS
  PLPPARSPTEPGPERRRSPGPAPGSPGELEEDLLLPGACPGADEAGGGAEGDSWEEEGFG
  SSSPVKSPAAPYFLGSSFSPVRCGGPGDASPRGCGARRAGEGRRSPRPDHPGTPPHKTFR
  KLRLFDTPHTPKSLLSKARGIDSSSVKLRGSSLFMDTEKSGKREFDVRQTPQVNINPFTP
  DSLLLHSSGQCRRRKRTYWNDSCGEDMEASDYELEDETRPAKRITITESNMKSRYTTEFH
  ELEKIGSGEFGSVFKCVKRLDGCIYAIKRSKKPLAGSVDEQNALREVYAHAVLGQHSHVV
  RYFSAWAEDDHMLIQNEYCNGGSLADAISENYRIMSYFKEAELKDLLLQVGRGLRYIHSM
  SLVHMDIKPSNIFISRTSIPNAASEEGDEDDWASNKVMFKIGDLGHVTRISSPQVEEGDS
  RFLANEVLQENYTHLPKADIFALALTVVCAAGAEPLPRNGDQWHEIRQGRLPRIPQVLSQ
  EFTELLKVMIHPDPERRPSAMALVKHSVLLSASRKSAEQLRIELNAEKFKNSLLQKELKK
  AQMAKAAAEERALFTDRMATRSTTQSNRTSRLIGKKMNRSVSLTIY
• Function: Acts as a negative regulator of entry into mitosis (G2 to M transition) by protecting the nucleus from cytoplasmically activated cyclin B1-complexed CDK1 before the onset of mitosis by mediating phosphorylation of CDK1 on 'Tyr-15'. Specifically phosphorylates and inactivates cyclin B1-complexed CDK1 reaching a maximum during G2 phase and a minimum as cells enter M phase. Phosphorylation of cyclin B1-CDK1 occurs exclusively on 'Tyr-15' and phosphorylation of monomeric CDK1 does not occur. Its activity increases during S and G2 phases and decreases at M phase when it is hyperphosphorylated. A correlated decrease in protein level occurs at M/G1 phase, probably due to its degradation.
• Uniprot ID: WEE1_HUMAN
• Ensembl ID: ENSG00000166483
• HGNC ID: HGNC:12761

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  RTDM: Regulation by the Disease Microenvironment

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 7 drug(s) in total

Cisplatin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Epidermoid carcinoma [1]

• Sensitive Disease: Epidermoid carcinoma [ICD-11: 2C31.Z]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: KB-3-1 cells; Lung; Homo sapiens (Human); CVCL_2088
• In Vitro Model: KB-CP.5 cells; Lung; Homo sapiens (Human); CVCL_IP04
• In Vitro Model: KB-CP20 cells; Lung; Homo sapiens (Human); CVCL_IP06
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of the cell cycle kinases WEE1 and CHk1 occurred commonly in cisplatin-resistant cells, miR-15/16/195/424/497 family sensitize cisplatin-resistant cells to apoptosis by targeting WEE1 and CHk1.

Fluorouracil

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Colon cancer [2]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Resistant Drug: Fluorouracil
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: Inhibition of miR195 sensitized resistant cells to 5-FU by downregulating WEE1 and CHk1.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Kidney cancer [3]

• Sensitive Disease: Kidney cancer [ICD-11: 2C90.1]
• Sensitive Drug: Fluorouracil
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: WEE1/Cdc2 signaling pathway; Activation; hsa04110
• In Vitro Model: 786-O cells; Kidney; Homo sapiens (Human); CVCL_1051
• In Vitro Model: HK-2 cells; Kidney; Homo sapiens (Human); CVCL_0302
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-381 increases sensitivity of 786-O cells to 5-FU by inhibitory WEE1 and increase of Cdc2activity.

LY2835219

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast cancer [4]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Resistant Drug: LY2835219
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Mechanism Description: WEE1 plays an important role in the G2/M checkpoint. It inhibits the entry of DNA-damaged cells into mitosis in coordination with CDK1. Though the involvement of WEE1 in inducing resistance to CDK4/6 inhibitors is unknown, inhibition of WEE1 has been shown to increase sensitivity to CDK4/6 inhibitors in resistant cells. As WEE1 is associated with a resistant phenotype in preclinical models, targeting the G2/M phase via the inhibition of WEE1 in combination with CDK4/6 inhibition could be a therapeutic option in overcoming resistance.

Palbociclib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast cancer [4]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Resistant Drug: Palbociclib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Mechanism Description: WEE1 plays an important role in the G2/M checkpoint. It inhibits the entry of DNA-damaged cells into mitosis in coordination with CDK1. Though the involvement of WEE1 in inducing resistance to CDK4/6 inhibitors is unknown, inhibition of WEE1 has been shown to increase sensitivity to CDK4/6 inhibitors in resistant cells. As WEE1 is associated with a resistant phenotype in preclinical models, targeting the G2/M phase via the inhibition of WEE1 in combination with CDK4/6 inhibition could be a therapeutic option in overcoming resistance.

Ribociclib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast cancer [4]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Resistant Drug: Ribociclib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Mechanism Description: WEE1 plays an important role in the G2/M checkpoint. It inhibits the entry of DNA-damaged cells into mitosis in coordination with CDK1. Though the involvement of WEE1 in inducing resistance to CDK4/6 inhibitors is unknown, inhibition of WEE1 has been shown to increase sensitivity to CDK4/6 inhibitors in resistant cells. As WEE1 is associated with a resistant phenotype in preclinical models, targeting the G2/M phase via the inhibition of WEE1 in combination with CDK4/6 inhibition could be a therapeutic option in overcoming resistance.

Temozolomide

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Disease Class: Glioma [5]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Sensitive Drug: Temozolomide
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SNB19 cells; Brain; Homo sapiens (Human); CVCL_0535
• In Vitro Model: T98G cells; Brain; Homo sapiens (Human); CVCL_0556
• In Vitro Model: SNB19 TR cells; Brain; Homo sapiens (Human); CVCL_0535
• In Vitro Model: T98G TR cells; Brain; Homo sapiens (Human); CVCL_0556
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT Assay; Wound healing assay; Transwell invasion assays
• Mechanism Description: miR26b reverses temozolomide resistance via targeting Wee1 in glioma cells. miR26b governed TR-mediate EMT partly due to governing its target Wee1.

Vincristine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Diffuse large B-cell lymphoma [6]

• Resistant Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Resistant Drug: Vincristine
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: OCI-Ly7 cells; N.A.; Homo sapiens (Human); CVCL_1881
• In Vitro Model: SU-DHL-5 cells; N.A.; Homo sapiens (Human); CVCL_1735
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Dose-response assays
• Mechanism Description: Down-regulation of miR-155 promotes vincristine resistance via upregulating Week1.

Investigative Drug(s) 1 drug(s) in total

MK1775

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Disease Class: Acute T-cell lymphocytic leukemia [7]

• Sensitive Disease: Acute T-cell lymphocytic leukemia [ICD-11: 2A90.5]
• Sensitive Drug: MK1775
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Jurkat cells; Pleural effusion; Homo sapiens (Human); CVCL_0065
• In Vitro Model: CCRF-CEM cells; Pleural effusion; Homo sapiens (Human); CVCL_0207
• In Vitro Model: MOLT4 cells; Bone marrow; Homo sapiens (Human); CVCL_0013
• In Vitro Model: DND41 cells; Pleural effusion; Homo sapiens (Human); CVCL_2022
• In Vitro Model: HPB-ALL cells; Peripheral blood; Homo sapiens (Human); CVCL_1820
• In Vitro Model: CUTLL1 cells; Pleural effusion; Homo sapiens (Human); CVCL_4966
• In Vitro Model: KOPTK1 cells; N.A.; Homo sapiens (Human); CVCL_4965
• In Vivo Model: NOD-Prkdcscid IL2Rgamma null NPG mice model; Mus musculus
• Experiment for Molecule Alteration: Western blotting assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: WEE1 inhibition sensitizes T-cell acute lymphoblastic leukemia cells to glutaminolysis inhibition.Elevated WEE1 expression driven by MYC poses the possibility that T-ALL cells may be particularly dependent on WEE1 for cell proliferation and survival. Indeed, a selective WEE1 inhibitor MK1775 as a single agent reduced cell viability in a dose-dependent manner in seven T-ALL cell lines, whereas the effect on normal BM cells was minimal.

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Brain cancer [ICD-11: 2A00]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Nervous tissue
• The Specified Disease: Brain cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 0.00E+00; Fold-change: 2.69E+00; Z-score: 4.79E+00
• The Studied Tissue: Brainstem tissue
• The Specified Disease: Glioma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 9.26E-02; Fold-change: 1.51E+00; Z-score: 3.26E+00
• The Studied Tissue: White matter
• The Specified Disease: Glioma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.77E-03; Fold-change: 7.74E-01; Z-score: 8.28E-01
• The Studied Tissue: Brainstem tissue
• The Specified Disease: Neuroectodermal tumor
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.82E-09; Fold-change: 2.88E+00; Z-score: 5.50E+00

Colon cancer [ICD-11: 2B90]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Colon
• The Specified Disease: Colon cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 4.92E-41; Fold-change: 5.36E-01; Z-score: 1.39E+00
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 1.47E-31; Fold-change: 6.65E-01; Z-score: 1.37E+00

Skin squamous cell carcinoma [ICD-11: 2C31]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Skin
• The Specified Disease: Skin squamous cell carcinoma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 6.50E-11; Fold-change: -3.83E-01; Z-score: -6.73E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 8.08E-14; Fold-change: -6.15E-01; Z-score: -8.53E-01

Breast cancer [ICD-11: 2C60]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Breast tissue
• The Specified Disease: Breast cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.38E-02; Fold-change: 1.14E-01; Z-score: 1.30E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 2.79E-01; Fold-change: -2.69E-01; Z-score: -2.33E-01

Kidney cancer [ICD-11: 2C90]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Kidney
• The Specified Disease: Kidney cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.46E-01; Fold-change: 2.80E-01; Z-score: 3.17E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 3.65E-04; Fold-change: 1.96E-01; Z-score: 3.19E-01

References

• Ref 1: Cisplatin sensitivity mediated by WEE1 and CHK1 is mediated by miR-155 and the miR-15 family. Cancer Res. 2012 Nov 15;72(22):5945-55. doi: 10.1158/0008-5472.CAN-12-1400. Epub 2012 Aug 31.
• Ref 2: MicroRNA-195 desensitizes HCT116 human colon cancer cells to 5-fluorouracil. Cancer Lett. 2018 Jan 1;412:264-271. doi: 10.1016/j.canlet.2017.10.022. Epub 2017 Nov 5.
• Ref 3: miR-381, a novel intrinsic WEE1 inhibitor, sensitizes renal cancer cells to 5-FU by up-regulation of Cdc2 activities in 786-O. J Chemother. 2013 Aug;25(4):229-38. doi: 10.1179/1973947813Y.0000000092. Epub 2013 May 7.
• Ref 4: Molecular mechanisms of resistance to CDK4/6 inhibitors in breast cancer: A review .Int J Cancer. 2019 Sep 1;145(5):1179-1188. doi: 10.1002/ijc.32020. Epub 2019 Jan 7. 10.1002/ijc.32020
• Ref 5: MiR-26b reverses temozolomide resistance via targeting Wee1 in glioma cells. Cell Cycle. 2017 Oct 18;16(20):1954-1964. doi: 10.1080/15384101.2017.1367071. Epub 2017 Sep 12.
• Ref 6: MicroRNA-155 controls vincristine sensitivity and predicts superior clinical outcome in diffuse large B-cell lymphoma. Blood Adv. 2019 Apr 9;3(7):1185-1196. doi: 10.1182/bloodadvances.2018029660.
• Ref 7: WEE1 inhibition induces glutamine addiction in T-cell acute lymphoblastic leukemia .Haematologica. 2021 Jul 1;106(7):1816-1827. doi: 10.3324/haematol.2019.231126. 10.3324/haematol.2019.231126