Strategic development of AZD1775, a Wee1 kinase inhibitor, for cancer therapy

References

• Otto T, Sicinski P. Cell cycle proteins as promising targets in cancer therapy. Nat Rev Cancer. 2017;17:93–115.
   PubMed Web of Science ®Google Scholar
• Ceccaldi R, Liu JC, Amunugama R, et al. Homologous-recombination-deficient tumours are dependent on Poltheta-mediated repair. Nature. 2015;518:258–262.
   PubMed Web of Science ®Google Scholar
• Patch AM, Christie EL, Etemadmoghadam D, et al. Whole-genome characterization of chemoresistant ovarian cancer. Nature. 2015;521:489–494.
   PubMed Web of Science ®Google Scholar
• Forment JV, O’Connor MJ. Targeting the replication stress response in cancer. Pharmacol Ther. 2018;188:155–167.
   PubMed Web of Science ®Google Scholar
• Russell P, Nurse P. Negative regulation of mitosis by wee1+, a gene encoding a protein kinase homolog. Cell. 1987;49:559–567. .
   PubMed Web of Science ®Google Scholar
• Aarts M, Sharpe R, Garcia-Murillas I, et al. Forced mitotic entry of S-phase cells as a therapeutic strategy induced by inhibition of WEE1. Cancer Discov. 2012;2:524–539.
   PubMed Web of Science ®Google Scholar
• Kogiso T, Nagahara H, Hashimoto E, et al. Efficient induction of apoptosis by wee1 kinase inhibition in hepatocellular carcinoma cells. PLoS One. 2014;9:e100495.
   PubMed Web of Science ®Google Scholar
• Mir SE, De Witt Hamer PC, Krawczyk PM, et al. In silico analysis of kinase expression identifies WEE1 as a gatekeeper against mitotic catastrophe in glioblastoma. Cancer Cell. 2010;18:244–257.
   PubMed Web of Science ®Google Scholar
• Harris PS, Venkataraman S, Alimova I, et al. Integrated genomic analysis identifies the mitotic checkpoint kinase WEE1 as a novel therapeutic target in medulloblastoma. Mol Cancer. 2014;13:72.
   PubMed Web of Science ®Google Scholar
• Leary A, Auguste A, Mesnage S. DNA damage response as a therapeutic target in gynecological cancers. Curr Opin Oncol. 2016;28:404–411.
   PubMed Web of Science ®Google Scholar
• Abroudi A, Samarasinghe S, Kulasiri D. A comprehensive complex systems approach to the study and analysis of mammalian cell cycle control system in the presence of DNA damage stress. J Theor Biol. 2017;429:204–228.
   PubMed Web of Science ®Google Scholar
• Bassermann F, Frescas D, Guardavaccaro D, et al. The Cdc14B-Cdh1-Plk1 axis controls the G2 DNA-damage-response checkpoint. Cell. 2008;134:256–267.
   PubMed Web of Science ®Google Scholar
• Kato S, Schwaederle M, Daniels GA, et al. Cyclin-dependent kinase pathway aberrations in diverse malignancies: clinical and molecular characteristics. Cell Cycle. 2015;14:1252–1259.
   PubMed Web of Science ®Google Scholar
• Visconti R, Della Monica R, Grieco D. Cell cycle checkpoint in cancer: a therapeutically targetable double-edged sword. J Exp Clin Cancer Res. 2016;35:153.
   PubMed Web of Science ®Google Scholar
• Kanska J, Zakhour M, Taylor-Harding B, et al. Cyclin E as a potential therapeutic target in high grade serous ovarian cancer. Gynecol Oncol. 2016;143:152–158.
   PubMed Web of Science ®Google Scholar
• Hegarat N, Rata S, Hochegger H. Bistability of mitotic entry and exit switches during open mitosis in mammalian cells. Bioessays. 2016;38:627–643.
   PubMed Web of Science ®Google Scholar
• Boutros R, Dozier C, Ducommun B. The when and wheres of CDC25 phosphatases. Curr Opin Cell Biol. 2006;18:185–191.
   PubMed Web of Science ®Google Scholar
• Vassilopoulos A, Tominaga Y, Kim HS, et al. WEE1 murine deficiency induces hyper-activation of APC/C and results in genomic instability and carcinogenesis. Oncogene. 2015;34:3023–3035.
   PubMed Web of Science ®Google Scholar
• Liu JC, Granieri L, Shrestha M, et al. Identification of CDC25 as a Common Therapeutic Target for Triple-Negative Breast Cancer. Cell Rep. 2018;23:112–126.
   PubMed Web of Science ®Google Scholar
• Schmidt M, Rohe A, Platzer C, et al. Regulation of G2/M Transition by Inhibition of WEE1 and PKMYT1 Kinases. Molecules. 2017;22:2045. doi:10.3390/molecules22122045.
   Web of Science ®Google Scholar
• Moseley JB. Wee1 and Cdc25: tools, pathways, mechanisms, questions. Cell Cycle. 2017;16:599–600.
   PubMed Web of Science ®Google Scholar
• Lucena R, Alcaide-Gavilan M, Anastasia SD, et al. Wee1 and Cdc25 are controlled by conserved PP2A-dependent mechanisms in fission yeast. Cell Cycle. 2017;16:428–435.
   PubMed Web of Science ®Google Scholar
• Iwai A, Bourboulia D, Mollapour M, et al. Combined inhibition of Wee1 and Hsp90 activates intrinsic apoptosis in cancer cells. Cell Cycle. 2012;11:3649–3655.
   PubMed Web of Science ®Google Scholar
• O’Connell MJ, Raleigh JM, Verkade HM, et al. Chk1 is a wee1 kinase in the G2 DNA damage checkpoint inhibiting cdc2 by Y15 phosphorylation. EMBO J. 1997;16:545–554.
   PubMed Web of Science ®Google Scholar
• Lee J, Kumagai A, Dunphy WG. Positive regulation of Wee1 by Chk1 and 14–3–3 proteins. Mol Biol Cell. 2001;12:551–563.
   PubMed Web of Science ®Google Scholar
• Katayama K, Fujita N, Tsuruo T. Akt/protein kinase B-dependent phosphorylation and inactivation of WEE1Hu promote cell cycle progression at G2/M transition. Mol Cell Biol. 2005;25:5725–5737.
   PubMed Web of Science ®Google Scholar
• Beck H, Nahse V, Larsen MS, et al. Regulators of cyclin-dependent kinases are crucial for maintaining genome integrity in S phase. J Cell Biol. 2010;188:629–638.
   PubMed Web of Science ®Google Scholar
• Lianga N, Williams EC, Kennedy EK, et al. A Wee1 checkpoint inhibits anaphase onset. J Cell Biol. 2013;201:843–862.
   PubMed Web of Science ®Google Scholar
• Mahajan K, Mahajan NP. WEE1 tyrosine kinase, a novel epigenetic modifier. Trends Genet. 2013;29:394–402.
   PubMed Web of Science ®Google Scholar
• Mahajan K, Fang B, Koomen JM, et al. H2B Tyr37 phosphorylation suppresses expression of replication-dependent core histone genes. Nat Struct Mol Biol. 2012;19:930–937.
   PubMed Web of Science ®Google Scholar
• Bartucci M, Svensson S, Romania P, et al. Therapeutic targeting of Chk1 in NSCLC stem cells during chemotherapy. Cell Death Differ. 2012;19:768–778.
   PubMed Web of Science ®Google Scholar
• Music D, Dahlrot RH, Hermansen SK, et al. Expression and prognostic value of the WEE1 kinase in gliomas. J Neurooncol. 2016;127:381–389.
   PubMed Web of Science ®Google Scholar
• Wang H, Huang M, Zhang DY, et al. Global profiling of signaling networks: study of breast cancer stem cells and potential regulation. Oncologist. 2011;16:966–979.
   PubMed Web of Science ®Google Scholar
• Magnussen GI, Holm R, Emilsen E, et al. High expression of Wee1 is associated with poor disease-free survival in malignant melanoma: potential for targeted therapy. PLoS One. 2012;7:e38254.
   PubMed Web of Science ®Google Scholar
• Slipicevic A, Holth A, Hellesylt E, et al. Wee1 is a novel independent prognostic marker of poor survival in post-chemotherapy ovarian carcinoma effusions. Gynecol Oncol. 2014;135:118–124.
   PubMed Web of Science ®Google Scholar
• Kreahling JM, Gemmer JY, Reed D, et al. MK1775, a selective Wee1 inhibitor, shows single-agent antitumor activity against sarcoma cells. Mol Cancer Ther. 2012;11:174–182.
   PubMed Web of Science ®Google Scholar
• PosthumaDeBoer J, Wurdinger T, Graat HC, et al. WEE1 inhibition sensitizes osteosarcoma to radiotherapy. BMC Cancer. 2011;11:156.
   PubMed Web of Science ®Google Scholar
• Magnussen GI, Hellesylt E, Nesland JM, et al. High expression of wee1 is associated with malignancy in vulvar squamous cell carcinoma patients. BMC Cancer. 2013;13:288.
   PubMed Web of Science ®Google Scholar
• De Witt Hamer PC, Mir SE, Noske D, et al. WEE1 kinase targeting combined with DNA-damaging cancer therapy catalyzes mitotic catastrophe. Clin Cancer Res. 2011;17:4200–4207.
   PubMed Web of Science ®Google Scholar
• Backert S, Gelos M, Kobalz U, et al. Differential gene expression in colon carcinoma cells and tissues detected with a cDNA array. Int J Cancer. 1999;82:868–874.
   PubMed Web of Science ®Google Scholar
• Kiviharju-Af Hallstrom TM, Jaamaa S, Monkkonen M, et al. Human prostate epithelium lacks Wee1A-mediated DNA damage-induced checkpoint enforcement. Proc Natl Acad Sci USA. 2007;104:7211–7216.
   PubMed Web of Science ®Google Scholar
• Yoshida T, Tanaka S, Mogi A, et al. The clinical significance of Cyclin B1 and Wee1 expression in non-small-cell lung cancer. Ann Oncol. 2004;15:252–256.
   PubMed Web of Science ®Google Scholar
• Wang Z, Fu S. An overview of tyrosine kinase inhibitors for the treatment of epithelial ovarian cancer. Expert Opin Investig Drugs. 2016;25:15–30.
   PubMed Web of Science ®Google Scholar
• Leach SD, Scatena CD, Keefer CJ, et al. Negative regulation of Wee1 expression and Cdc2 phosphorylation during p53-mediated growth arrest and apoptosis. Cancer Res. 1998;58:3231–3236.
   PubMed Web of Science ®Google Scholar
• Tong Y, Torrent M, Florjancic AS, et al. Pyrimidine-based tricyclic molecules as potent and orally efficacious inhibitors of wee1 kinase. ACS Med Chem Lett. 2015;6:58–62.
   PubMed Web of Science ®Google Scholar
• Wright G, Golubeva V, Remsing Rix LL, et al. Dual targeting of WEE1 and PLK1 by AZD1775 elicits single agent cellular anticancer activity. ACS Chem Biol. 2017;12:1883–1892.
   PubMed Web of Science ®Google Scholar
• Zhu JY, Cuellar RA, Berndt N, et al. Structural basis of Wee kinases functionality and inactivation by diverse small molecule inhibitors. J Med Chem. 2017;60:7863–7875.
   PubMed Web of Science ®Google Scholar
• Metz JT, Johnson EF, Soni NB, et al. Navigating the kinome. Nat Chem Biol. 2011;7:200–202.
   PubMed Web of Science ®Google Scholar
• Geenen JJJ, Schellens JHM. Molecular pathways: targeting the protein kinase Wee1 in cancer. Clin Cancer Res. 2017;23:4540–4544.
   PubMed Web of Science ®Google Scholar
• Lescarbeau RS, Lei L, Bakken KK, et al. Quantitative phosphoproteomics reveals Wee1 kinase as a therapeutic target in a model of proneural glioblastoma. Mol Cancer Ther. 2016;15:1332–1343.
   PubMed Web of Science ®Google Scholar
• Carrassa L, Damia G. DNA damage response inhibitors: mechanisms and potential applications in cancer therapy. Cancer Treat Rev. 2017;60:139–151.
   PubMed Web of Science ®Google Scholar
• Aarts M, Bajrami I, Herrera-Abreu MT, et al. Functional genetic screen identifies increased sensitivity to WEE1 inhibition in cells with defects in fanconi anemia and HR pathways. Mol Cancer Ther. 2015;14:865–876.
   PubMed Web of Science ®Google Scholar
• Sen T, Tong P, Diao L, et al. Targeting AXL and mTOR pathway overcomes primary and acquired resistance to WEE1 inhibition in small-cell lung cancer. Clin Cancer Res. 2017;23:6239–6253.
   PubMed Web of Science ®Google Scholar
• Richer AL, Cala JM, O’Brien K, et al. WEE1 kinase inhibitor AZD1775 has preclinical efficacy in LKB1-deficient non-small cell lung cancer. Cancer Res. 2017;77:4663–4672.
   PubMed Web of Science ®Google Scholar
• Brandsma I, Fleuren EDG, Williamson CT, et al. Directing the use of DDR kinase inhibitors in cancer treatment. Expert Opin Investig Drugs. 2017;26:1341–1355.
   PubMed Web of Science ®Google Scholar
• Ku BM, Bae YH, Koh J, et al. Mutational status of TP53 defines the efficacy of Wee1 inhibitor AZD1775 in KRAS-mutant non-small cell lung cancer. Oncotarget. 2017;8:67526–67537.
   PubMedGoogle Scholar
• Rajeshkumar NV, De Oliveira E, Ottenhof N, et al. MK-1775, a potent Wee1 inhibitor, synergizes with gemcitabine to achieve tumor regressions, selectively in p53-deficient pancreatic cancer xenografts. Clin Cancer Res. 2011;17:2799–2806.
   PubMed Web of Science ®Google Scholar
• Hirai H, Iwasawa Y, Okada M, et al. Small-molecule inhibition of Wee1 kinase by MK-1775 selectively sensitizes p53-deficient tumor cells to DNA-damaging agents. Mol Cancer Ther. 2009;8:2992–3000.
   PubMed Web of Science ®Google Scholar
• Bridges KA, Hirai H, Buser CA, et al. MK-1775, a novel Wee1 kinase inhibitor, radiosensitizes p53-defective human tumor cells. Clin Cancer Res. 2011;17:5638–5648.
   PubMed Web of Science ®Google Scholar
• Zhang M, Dominguez D, Chen S, et al. WEE1 inhibition by MK1775 as a single-agent therapy inhibits ovarian cancer viability. Oncol Lett. 2017;14:3580–3586.
   PubMed Web of Science ®Google Scholar
• Guertin AD, Li J, Liu Y, et al. Preclinical evaluation of the WEE1 inhibitor MK-1775 as single-agent anticancer therapy. Mol Cancer Ther. 2013;12:1442–1452.
   PubMed Web of Science ®Google Scholar
• Mueller S, Hashizume R, Yang X, et al. Targeting Wee1 for the treatment of pediatric high-grade gliomas. Neuro Oncol. 2014;16:352–360.
   PubMed Web of Science ®Google Scholar
• Van Linden AA, Baturin D, Ford JB, et al. Inhibition of Wee1 sensitizes cancer cells to antimetabolite chemotherapeutics in vitro and in vivo, independent of p53 functionality. Mol Cancer Ther. 2013;12:2675–2684.
   PubMed Web of Science ®Google Scholar
• Webster PJ, Littlejohns AT, Gaunt HJ, et al. AZD1775 induces toxicity through double-stranded DNA breaks independently of chemotherapeutic agents in p53-mutated colorectal cancer cells. Cell Cycle. 2017;16:2176–2182.
   PubMed Web of Science ®Google Scholar
• Cuneo KC, Morgan MA, Davis MA, et al. Wee1 kinase inhibitor AZD1775 radiosensitizes hepatocellular carcinoma regardless of TP53 mutational status through induction of replication stress. Int J Radiat Oncol Biol Phys. 2016;95:782–790.
   PubMed Web of Science ®Google Scholar
• Yang Y, Gao Y, Mutter-Rottmayer L, et al. DNA repair factor RAD18 and DNA polymerase polkappa confer tolerance of oncogenic DNA replication stress. J Cell Biol. 2017;216:3097–3115.
   PubMed Web of Science ®Google Scholar
• Toledo CM, Ding Y, Hoellerbauer P, et al. Genome-wide CRISPR-Cas9 screens reveal loss of redundancy between PKMYT1 and WEE1 in glioblastoma stem-like cells. Cell Rep. 2015;13:2425–2439.
   PubMed Web of Science ®Google Scholar
• Pfister SX, Markkanen E, Jiang Y, et al. Inhibiting WEE1 selectively kills histone H3K36me3-deficient cancers by dNTP starvation. Cancer Cell. 2015;28:557–568.
   PubMed Web of Science ®Google Scholar
• Mahajan NP, Malla P, Bhagwat S, et al. WEE1 epigenetically modulates 5-hmC levels by pY37-H2B dependent regulation of IDH2 gene expression. Oncotarget. 2017;8:106352–106368.
   PubMedGoogle Scholar
• Lindemann A, Takahashi H, Patel AA, et al. Targeting the DNA damage response in OSCC with TP53 mutations. J Dent Res. 2018;97:635–644.
   PubMed Web of Science ®Google Scholar
• Osman AA, Monroe MM, Ortega Alves MV, et al. Wee-1 kinase inhibition overcomes cisplatin resistance associated with high-risk TP53 mutations in head and neck cancer through mitotic arrest followed by senescence. Mol Cancer Ther. 2015;14:608–619.
   PubMed Web of Science ®Google Scholar
• Tanaka N, Patel AA, Wang J, et al. Wee-1 kinase inhibition sensitizes high-risk HPV+ HNSCC to apoptosis accompanied by downregulation of MCl-1 and XIAP antiapoptotic proteins. Clin Cancer Res. 2015;21:4831–4844.
   PubMed Web of Science ®Google Scholar
• Stewart E, Federico SM, Chen X, et al. Orthotopic patient-derived xenografts of paediatric solid tumours. Nature. 2017;549:96–100.
   PubMed Web of Science ®Google Scholar
• Jhuraney A, Woods NT, Wright G, et al. PAXIP1 potentiates the combination of WEE1 Inhibitor AZD1775 and platinum agents in lung cancer. Mol Cancer Ther. 2016;15:1669–1681.
   PubMed Web of Science ®Google Scholar
• Zhao W, Liu S, Dou Q, et al. The role and mechanism of WEE1 on the cisplatin resistance reversal of the HepG2/DDP human hepatic cancer cell line. Oncol Lett. 2015;10:3081–3086.
   PubMed Web of Science ®Google Scholar
• Indovina P, Marcelli E, Di Marzo D, et al. Abrogating G(2)/M checkpoint through WEE1 inhibition in combination with chemotherapy as a promising therapeutic approach for mesothelioma. Cancer Biol Ther. 2014;15:380–388.
   PubMed Web of Science ®Google Scholar
• Ford JB, Baturin D, Burleson TM, et al. AZD1775 sensitizes T cell acute lymphoblastic leukemia cells to cytarabine by promoting apoptosis over DNA repair. Oncotarget. 2015;6:28001–28010.
   PubMedGoogle Scholar
• Kausar T, Schreiber JS, Karnak D, et al. Sensitization of pancreatic cancers to gemcitabine chemoradiation by WEE1 kinase inhibition depends on homologous recombination repair. Neoplasia. 2015;17:757–766.
   PubMed Web of Science ®Google Scholar
• Kreahling JM, Foroutan P, Reed D, et al. Wee1 inhibition by MK-1775 leads to tumor inhibition and enhances efficacy of gemcitabine in human sarcomas. PLoS One. 2013;8:e57523.
   PubMed Web of Science ®Google Scholar
• Kim HY, Cho Y, Kang H, et al. Targeting the WEE1 kinase as a molecular targeted therapy for gastric cancer. Oncotarget. 2016;7:49902–49916.
   PubMedGoogle Scholar
• Hirai H, Arai T, Okada M, et al. MK-1775, a small molecule Wee1 inhibitor, enhances anti-tumor efficacy of various DNA-damaging agents, including 5-fluorouracil. Cancer Biol Ther. 2010;9:514–522.
   PubMed Web of Science ®Google Scholar
• Lewis CW, Jin Z, Macdonald D, et al. Prolonged mitotic arrest induced by Wee1 inhibition sensitizes breast cancer cells to paclitaxel. Oncotarget. 2017;8:73705–73722.
   PubMedGoogle Scholar
• Pokorny JL, Calligaris D, Gupta SK, et al. The efficacy of the Wee1 inhibitor MK-1775 combined with temozolomide is limited by heterogeneous distribution across the blood-brain barrier in glioblastoma. Clin Cancer Res. 2015;21:1916–1924.
   PubMed Web of Science ®Google Scholar
• Ma H, Takahashi A, Sejimo Y, et al. Targeting of carbon ion-induced G2 checkpoint activation in lung cancer cells using Wee-1 inhibitor MK-1775. Radiat Res. 2015;184:660–669.
   PubMed Web of Science ®Google Scholar
• Sarcar B, Kahali S, Prabhu AH, et al. Targeting radiation-induced G(2) checkpoint activation with the Wee-1 inhibitor MK-1775 in glioblastoma cell lines. Mol Cancer Ther. 2011;10:2405–2414.
   PubMed Web of Science ®Google Scholar
• Sakurikar N, Thompson R, Montano R, et al. A subset of cancer cell lines is acutely sensitive to the Chk1 inhibitor MK-8776 as monotherapy due to CDK2 activation in S phase. Oncotarget. 2016;7:1380–1394.
   PubMed Web of Science ®Google Scholar
• Tanaka N, Patel AA, Tang L, et al. Replication stress leading to apoptosis within the S-phase contributes to synergism between vorinostat and AZD1775 in HNSCC harboring high-risk TP53 mutation. Clin Cancer Res. 2017;23:6541–6554.
   PubMed Web of Science ®Google Scholar
• Zheng H, Shao F, Martin S, et al. WEE1 inhibition targets cell cycle checkpoints for triple negative breast cancers to overcome cisplatin resistance. Sci Rep. 2017;7:43517.
   PubMed Web of Science ®Google Scholar
• Clausse V, Goloudina AR, Uyanik B, et al. Wee1 inhibition potentiates Wip1-dependent p53-negative tumor cell death during chemotherapy. Cell Death Dis. 2016;7:e2195.
   PubMed Web of Science ®Google Scholar
• Chila R, Basana A, Lupi M, et al. Combined inhibition of Chk1 and Wee1 as a new therapeutic strategy for mantle cell lymphoma. Oncotarget. 2015;6:3394–3408.
   PubMed Web of Science ®Google Scholar
• Li Y, Saini P, Sriraman A, et al. Mdm2 inhibition confers protection of p53-proficient cells from the cytotoxic effects of Wee1 inhibitors. Oncotarget. 2015;6:32339–32352.
   PubMed Web of Science ®Google Scholar
• Francis AM, Alexander A, Liu Y, et al. CDK4/6 inhibitors sensitize rb-positive sarcoma cells to Wee1 kinase inhibition through reversible cell-cycle arrest. Mol Cancer Ther. 2017;16:1751–1764.
   PubMed Web of Science ®Google Scholar
• Drean A, Williamson CT, Brough R, et al. Modeling therapy resistance in BRCA1/2-mutant cancers. Mol Cancer Ther. 2017;16:2022–2034.
   PubMed Web of Science ®Google Scholar
• Karnak D, Engelke CG, Parsels LA, et al. Combined inhibition of Wee1 and PARP1/2 for radiosensitization in pancreatic cancer. Clin Cancer Res. 2014;20:5085–5096.
   PubMed Web of Science ®Google Scholar
• Ruiz S, Mayor-Ruiz C, Lafarga V, et al. A genome-wide CRISPR screen identifies CDC25A as a determinant of sensitivity to ATR inhibitors. Mol Cell. 2016;62:307–313.
   PubMed Web of Science ®Google Scholar
• Busch CJ, Kroger MS, Jensen J, et al. G2-checkpoint targeting and radiosensitization of HPV/p16-positive HNSCC cells through the inhibition of Chk1 and Wee1. Radiother Oncol. 2017;122:260–266.
   PubMed Web of Science ®Google Scholar
• Restelli V, Vagni M, Arribas AJ, et al. Inhibition of CHK1 and WEE1 as a new therapeutic approach in diffuse large B cell lymphomas with MYC deregulation. Br J Haematol. 2018;181:129–133.
   PubMed Web of Science ®Google Scholar
• Hauge S, Naucke C, Hasvold G, et al. Combined inhibition of Wee1 and Chk1 gives synergistic DNA damage in S-phase due to distinct regulation of CDK activity and CDC45 loading. Oncotarget. 2017;8:10966–10979.
   PubMedGoogle Scholar
• Carrassa L, Chila R, Lupi M, et al. Combined inhibition of Chk1 and Wee1: in vitro synergistic effect translates to tumor growth inhibition in vivo. Cell Cycle. 2012;11:2507–2517.
   PubMed Web of Science ®Google Scholar
• Wang G, Niu X, Zhang W, et al. Synergistic antitumor interactions between MK-1775 and panobinostat in preclinical models of pancreatic cancer. Cancer Lett. 2015;356:656–668.
   PubMed Web of Science ®Google Scholar
• Qi W, Zhang W, Edwards H, et al. Synergistic anti-leukemic interactions between panobinostat and MK-1775 in acute myeloid leukemia ex vivo. Cancer Biol Ther. 2015;16:1784–1793.
   PubMed Web of Science ®Google Scholar
• Zhou L, Zhang Y, Chen S, et al. A regimen combining the Wee1 inhibitor AZD1775 with HDAC inhibitors targets human acute myeloid leukemia cells harboring various genetic mutations. Leukemia. 2015;29:807–818.
   PubMed Web of Science ®Google Scholar
• Chen G, Zhang B, Xu H, et al. Suppression of sirt1 sensitizes lung cancer cells to WEE1 inhibitor MK-1775-induced DNA damage and apoptosis. Oncogene. 2017;36:6863–6872.
   PubMed Web of Science ®Google Scholar
• Wu S, Wang S, Gao F, et al. Activation of WEE1 confers resistance to PI3K inhibition in glioblastoma. Neuro Oncol. 2018;20:78–91.
   PubMed Web of Science ®Google Scholar
• Kuzu OF, Gowda R, Sharma A, et al. Identification of WEE1 as a target to make AKT inhibition more effective in melanoma. Cancer Biol Ther. 2018;19:53–62.
   PubMed Web of Science ®Google Scholar
• Hai J, Liu S, Bufe L, et al. Synergy of WEE1 and mTOR inhibition in mutant KRAS-driven lung cancers. Clin Cancer Res. 2017;23:6993–7005.
   PubMed Web of Science ®Google Scholar
• Dinavahi SS, Noory MA, Gowda R, et al. Moving synergistically acting drug combinations to the clinic by comparing sequential versus simultaneous drug administrations. Mol Pharmacol. 2018;93:190–196.
   PubMed Web of Science ®Google Scholar
• Johnson TS, Terrell CE, Millen SH, et al. Etoposide selectively ablates activated T cells to control the immunoregulatory disorder hemophagocytic lymphohistiocytosis. J Immunol. 2014;192:84–91.
   PubMed Web of Science ®Google Scholar
• McNally JP, Millen SH, Chaturvedi V, et al. Manipulating DNA damage-response signaling for the treatment of immune-mediated diseases. Proc Natl Acad Sci USA. 2017;114:E4782–E4791.
   PubMed Web of Science ®Google Scholar
• Watanabe M, Moon KD, Vacchio MS, et al. Downmodulation of tumor suppressor p53 by T cell receptor signaling is critical for antigen-specific CD4(+) T cell responses. Immunity. 2014;40:681–691.
   PubMed Web of Science ®Google Scholar
• Ghiasi N, Habibagahi M, Rosli R, et al. Tumor suppressive effects of WEE1 gene silencing could not enhance immunopotentiation effects of CD80 and 4–1BBL co-stimulation in human T cells. J Cancer Res Ther. 2015;11:708–716.
   PubMed Web of Science ®Google Scholar
• Fernando RI, Litzinger M, Trono P, et al. The T-box transcription factor brachyury promotes epithelial-mesenchymal transition in human tumor cells. J Clin Invest. 2010;120:533–544.
   PubMed Web of Science ®Google Scholar
• Hamilton DH, Huang B, Fernando RI, et al. WEE1 inhibition alleviates resistance to immune attack of tumor cells undergoing epithelial-mesenchymal transition. Cancer Res. 2014;74:2510–2519.
   PubMed Web of Science ®Google Scholar
• Li J, Wu J, Bao X, et al. Quantitative and mechanistic understanding of AZD1775 penetration across human blood-brain barrier in glioblastoma patients using an IVIVE-PBPK modeling approach. Clin Cancer Res. 2017;23:7454–7466.
   PubMed Web of Science ®Google Scholar
• Do K, Wilsker D, Ji J, et al. Phase I study of single-agent AZD1775 (MK-1775), a Wee1 kinase inhibitor, in patients with refractory solid tumors. J Clin Oncol. 2015;33:3409–3415.
   PubMed Web of Science ®Google Scholar
• Leijen S, van Geel RM, Pavlick AC, et al. Phase I study evaluating WEE1 inhibitor AZD1775 as monotherapy and in combination with gemcitabine, cisplatin, or carboplatin in patients with advanced solid tumors. J Clin Oncol. 2016;34:4371–4380.
   PubMed Web of Science ®Google Scholar
• Leijen S, Van Geel RM, Sonke GS, et al. Phase II study of wee1 inhibitor AZD1775 plus carboplatin in patients with TP53-mutated ovarian cancer refractory or resistant to first-line therapy within 3 months. J Clin Oncol. 2016;34:4354–4361.
   PubMed Web of Science ®Google Scholar
• Mendez E, Rodriguez CP, Kao M, et al. A phase I clinical trial of AZD1775 in combination with neoadjuvant weekly docetaxel and cisplatin before definitive therapy in head and neck squamous cell carcinoma. Clin Cancer Res. 2018;24:2740–2748.
   Web of Science ®Google Scholar
• Oza AM, Weberpals JI, Provencher DM, et al. An international, biomarker-directed, randomized, phase II trial of AZD1775 plus paclitaxel and carboplatin (P/C) for the treatment of women with platinum-sensitive, TP53-mutant ovarian cancer. J Clin Oncol. 2015;33(suppl; abstr 5506).
   PubMedGoogle Scholar
• Lheureux S, Weberpals JI, Hendrickson AEW, et al. A randomized, placebo-controlled phase II trial comparing gemcitabine monotherapy to gemcitabine in combination with AZD 1775 (MK 1775) in women with recurrent, platinum-resistant epithelial ovarian, primary peritoneal, or fallopian tube cancers: trial of princess margaret, Mayo, Chicago, and California consortia. J Clin Oncol. 2015;33(suppl; abstr TPS5613).
   Google Scholar
• Glorieux M, Dok R, Nuyts S. Novel DNA targeted therapies for head and neck cancers: clinical potential and biomarkers. Oncotarget. 2017;8:81662–81678.
   PubMedGoogle Scholar
• Pappano WN, Zhang Q, Tucker LA, et al. Genetic inhibition of the atypical kinase Wee1 selectively drives apoptosis of p53 inactive tumor cells. BMC Cancer. 2014;14:430.
   PubMed Web of Science ®Google Scholar
• Friedman J, Morisada M, Sun L, et al. Inhibition of WEE1 kinase and cell cycle checkpoint activation sensitizes head and neck cancers to natural killer cell therapies. J Immunother Cancer. 2018;6:59.
   PubMed Web of Science ®Google Scholar
• Hamilton DH, McCampbell KK, Palena C. Loss of the cyclin-dependent kinase inhibitor 1 in the context of brachyury-mediated phenotypic plasticity drives tumor resistance to immune attack. Front Oncol. 2018;8:143.
   PubMed Web of Science ®Google Scholar