Skip to main content

Advertisement

SpringerLink
Log in

Wee1 kinase inhibitor AZD1775 potentiates CD8+ T cell-dependent antitumour activity via dendritic cell activation following a single high dose of irradiation

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

As standard treatments for cancer, DNA-damaging chemotherapeutic agents and irradiation therapy improve survival in patients with various cancers. Wee1, a kinase associated with the cell cycle, causes G2/M cell cycle arrest to allow repair of injured DNA in cancer cells, and a Wee1 inhibitor has been confirmed to lead to apoptosis in cancer cells. Recently, there has been renewed interest in exploring the immune environment which plays a significant role in tumour suppression. A Wee1 inhibitor combined with radiotherapy has been tested in lung, pancreatic, and prostate cancer and melanoma in vivo or in vitro. There is still no research evaluating the immunoregulatory effects of AZD1775 plus high-dose irradiation (IR) in vivo. T cell killing and CD8+ T cell depletion assays demonstrated that the combination of AZD1775 and IR delayed tumour growth in breast cancer mouse models. Additionally, combination treatment also suppressed the expression of PD-L1, a co-inhibitor, through the STAT3-IRF1 axis. The importance and originality of this study are that it explores the internal and external mechanisms of AZD1775 combined with a single high dose of IR and provides a rationale for applying the combination therapy described above in a clinical trial.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Mantovani A, Ponzetta A, Inforzato A, Jaillon S. Innate immunity, inflammation and tumour progression: double-edged swords. J Intern Med. 2019;285:524–32.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Adriana A, Antonino B, Noonan MD, Lorenzo M. Contribution to tumor angiogenesis from innate immune cells within the tumor microenvironment: implications for immunotherapy. Front Immunol. 2018;9:527.

    Article  CAS  Google Scholar 

  3. Tugues S, Ducimetiere L, Friebel E, et al. Innate lymphoid cells as regulators of the tumor microenvironment. Semin Immunol. 2019;41:101270.

    Article  PubMed  CAS  Google Scholar 

  4. Hanahan D, Coussens LM. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell. 2012;21:309–22.

    Article  PubMed  CAS  Google Scholar 

  5. Nirilanto R, Ellen A. Characterization of the tumor microenvironment and tumor-stroma interaction by non-invasive preclinical imaging. Front Oncol. 2017;7:3.

    Google Scholar 

  6. Barcellos-Hoff MH, Park C, Wright EG. Radiation and the microenvironment—tumorigenesis and therapy. Nat Rev Cancer. 2005;5:867–75.

    Article  PubMed  CAS  Google Scholar 

  7. Twyman-Saint Victor C, Rech AJ, Maity A, Rengan R, Pauken KE, Stelekati E, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature. 2015;520:373–7.

    Article  PubMed  CAS  Google Scholar 

  8. Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR, et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Investig. 2014;124:687–95.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  9. Kachikwu EL, Iwamoto KS, Liao YP, DeMarco JJ, Agazaryan N, Economou JS, et al. Radiation enhances regulatory T cell representation. Int J Radiat Oncol Biol Phys. 2011;81:1128–35.

    Article  PubMed  Google Scholar 

  10. Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L, et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: "N1" versus "N2" TAN. Cancer Cell. 2009;16:183–94.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Tsai CS, Chen FH, Wang CC, Huang HL, Jung SM, Wu CJ, et al. Macrophages from irradiated tumors express higher levels of iNOS, arginase-I and COX-2, and promote tumor growth. Int J Radiat Oncol Biol Phys. 2007;68:499–507.

    Article  PubMed  CAS  Google Scholar 

  12. Xu J, Escamilla J, Mok S, David J, Priceman S, West B, et al. CSF1R signaling blockade stanches tumor-infiltrating myeloid cells and improves the efficacy of radiotherapy in prostate cancer. Cancer Res. 2013;73:2782–94.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Formenti SC, Demaria S. Combining radiotherapy and cancer immunotherapy: a paradigm shift. J Natl Cancer Inst. 2013;105:256–65.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Falcke SE, Rühle PF, Deloch L, Fietkau R, Frey B, Gaipl US. Clinically relevant radiation exposure differentially impacts forms of cell death in human cells of the innate and adaptive immune system. Int J Mol Sci. 2018;19:3574.

    Article  PubMed Central  Google Scholar 

  15. Chajon E, Castelli J, Marsiglia H, Crevoisier RD. The synergistic effect of radiotherapy and immunotherapy: a promising but not simple partnership. Crit Rev Oncol/Hematol. 2017;111:124–32.

    Article  Google Scholar 

  16. Toulany M, Targeting DNA. Double-strand break repair pathways to improve radiotherapy response. Genes. 2019;10:25.

    Article  PubMed Central  CAS  Google Scholar 

  17. Baskar R, Dai J, Wenlong N, Yeo R, Yeoh KW. Biological response of cancer cells to radiation treatment. Front Mol Biosci. 2014;1:24.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Hellevik T, Martinez-Zubiaurre I. Radiotherapy and the tumor stroma: the importance of dose and fractionation. Front Oncol. 2014;4:1.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Wang S-J, Haffty B. Radiotherapy as a new player in immuno-oncology. Cancers. 2018;10:515.

    Article  PubMed Central  CAS  Google Scholar 

  20. Arnold KM, Flynn NJ, Raben A, Romak L, Yu Y, Dicker AP, et al. The impact of radiation on the tumor microenvironment: effect of dose and fractionation schedules. Cancer Growth Metastasis. 2018;11:1–17.

    Article  Google Scholar 

  21. Tsoutsou PG, Zaman K, Lluesma SM, Cagnon L, Kandalaft L, Vozenin M-C. Emerging opportunities of radiotherapy combined with immunotherapy in the era of breast cancer heterogeneity. Front Oncol. 2018;8:609.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Meziani L, Deutsch E, Mondini M. Macrophages in radiation injury: a new therapeutic target. Oncoimmunology. 2018;7(10):e1494488.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Sato H, Niimi A, Yasuhara T, Permata TBM, Hagiwara Y, Isono M, et al. DNA double-strand break repair pathway regulates PD-L1 expression in cancer cells. Nat Commun. 2017;8:1751.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    Article  PubMed  CAS  Google Scholar 

  25. Kogiso T, Nagahara H, Hashimoto E, Ariizumi S, Yamamoto M, Shiratori K. Efficient induction of apoptosis by wee1 kinase inhibition in hepatocellular carcinoma cells. PLoS ONE. 2014;9:e100495.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Mir SE, De Witt Hamer PC, Krawczyk PM, Balaj L, Claes A, Niers JM, et al. In silico analysis of kinase expression identifies WEE1 as a gatekeeper against mitotic catastrophe in glioblastoma. Cancer Cell. 2010;18:244–57.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Osman AA, Monroe MM, Ortega Alves MV, Patel AA, Katsonis P, Fitzgerald AL, 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;14:608–19.

    Article  PubMed  CAS  Google Scholar 

  28. Ford JB, Baturin D, Burleson TM, Van Linden AA, Kim YM, Porter CC. AZD1775 sensitizes T cell acute lymphoblastic leukemia cells to cytarabine by promoting apoptosis over DNA repair. Oncotarget. 2015;6:28001–10.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Kausar T, Schreiber JS, Karnak D, Parsels LA, Parsels JD, Davis MA, et al. Sensitization of pancreatic cancers to gemcitabine chemoradiation by WEE1 kinase inhibition depends on homologous recombination repair. Neoplasia. 2015;17:757–66.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Hirai H, Arai T, Okada M, Nishibata T, Kobayashi M, Sakai N, 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;9:514–22.

    Article  PubMed  CAS  Google Scholar 

  31. Lewis CW, Jin Z, Macdonald D, Wei W, Qian XJ, Choi WS, et al. Prolonged mitotic arrest induced by Wee1 inhibition sensitizes breast cancer cells to paclitaxel. Oncotarget. 2017;8:73705–22.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Pokorny JL, Calligaris D, Gupta SK, Iyekegbe DO, Mueller D, Bakken KK, 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;21:1916–24.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Ma H, Takahashi A, Sejimo Y, Adachi A, Kubo N, Isono M, et al. Targeting of carbon ion-induced G2 checkpoint activation in lung cancer cells using Wee-1 inhibitor MK-1775. Radiat Res. 2015;184:660–9.

    Article  PubMed  CAS  Google Scholar 

  34. Bridges KA, Hirai H, Buser CA, Brooks C, Liu H, Buchholz TA, et al. MK-1775, a novel Wee1 kinase inhibitor, radiosensitizes p53-defective human tumor cells. Clin Cancer Res. 2011;17:5638–48.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Sun L, Moore E, Berman R, Clavijo PE, Saleh A, Chen Z, et al. WEE1 kinase inhibition reverses G2/M cell cycle checkpoint activation to sensitize cancer cells to immunotherapy. Oncoimmunology. 2018;7:e1488359.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-associated B7–H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8:793–800.

    Article  PubMed  CAS  Google Scholar 

  37. Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol. 2012;24:207–12.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Chu GJ, van Zandwijk N, Rasko JEJ. The immune microenvironment in mesothelioma: mechanisms of resistance to immunotherapy. Front Oncol. 2019;9:1366.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Friedman J, Morisada M, Sun L, Moore EC, Padget M, Hodge JW, 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.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Leijen S, van Geel RM, Sonke GS, de Jong D, Rosenberg EH, Marchetti S, 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;34:4354–61.

    Article  PubMed  CAS  Google Scholar 

  41. Patel P, Sun L, Robbins Y, Clavijo PE, Friedman J, Silvin C, et al. Enhancing direct cytotoxicity and response to immune checkpoint blockade following ionizing radiation with Wee1 kinase inhibition. Oncoimmunology. 2019;8:e1638207.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Cuneo KC, Morgan MA, Davis MA, Parcels LA, Parcels J, Karnak D, 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;95:782–90.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Rosenbaum MW, Bledsoe JR, Morales-Oyarvide V, Huynh TG, Mino-Kenudson M. PD-L1 expression in colorectal cancer is associated with microsatellite instability, BRAF mutation, medullary morphology and cytotoxic tumor-infiltrating lymphocytes. Mod Pathol. 2016;29:1104–12.

    Article  PubMed  CAS  Google Scholar 

  44. Permata TBM, Hagiwara Y, Sato H, Yasuhara T, Oike T, Gondhowiardjo S, et al. Base excision repair regulates PD-L1 expression in cancer cells. Oncogene. 2019;38:4452–66.

    Article  PubMed  CAS  Google Scholar 

Download references

Funding

This work was supported by grants from The National Natural Sciences Foundation of China (Grant Nos. 81602678 and 81472797) and Natural Science Foundation of Tianjin (Grant No. 17JCQNJC12300).

Author information

Authors and Affiliations

  1. Key Laboratory of Cancer Prevention and Therapy, Tianjin Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, People’s Republic of China

    Bin Wang, Zhiyong Yuan & Zhen Tao

  2. Department of Radiation Oncology, Xijing Hospital, The Fourth Military Medical University, No. 127, Chang Le West Road, Xi’an, 710032, China

    Bin Wang

  3. Department of Pathology, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China

    Lin Sun

  4. Department of Radiation Oncology and Cyberknife Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China

    Zhiyong Yuan & Zhen Tao

Authors
  1. Bin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lin Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhiyong Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhen Tao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

ZY and ZT conceived the study. BW carried out the experiments, analysed the data, and wrote the manuscript. LS participated in the experimental direction. All authors read and approved the final version of the manuscript.

Corresponding authors

Correspondence to Zhiyong Yuan or Zhen Tao.

Ethics declarations

Conflict of interest

There are no potential conflicts of interest.

Research involved in human and animal rights

This study was approved by the independent ethics committees at our hospital (no. Ek2019072 and no. LLSP2019-159).

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, B., Sun, L., Yuan, Z. et al. Wee1 kinase inhibitor AZD1775 potentiates CD8+ T cell-dependent antitumour activity via dendritic cell activation following a single high dose of irradiation. Med Oncol 37, 66 (2020). https://doi.org/10.1007/s12032-020-01390-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-020-01390-w

Keywords

Search

Navigation