Advertisement

Prexasertib, a checkpoint kinase inhibitor: from preclinical data to clinical development

  • Gesuino AngiusEmail author
  • Silverio Tomao
  • Valeria Stati
  • Patrizia Vici
  • Vincenzo Bianco
  • Federica Tomao
Review Article
  • 169 Downloads

Abstract

Checkpoint kinases 1 and 2 (CHK1 and CHK2) are important multifunctional proteins of the kinase family. Their main function is to regulate DNA replication and DNA damage response. If a cell is exposed to exogenous damage to its DNA, CHK1/CHK2 stops the cell cycle to give time to the cellular mechanisms to repair DNA breakage and apoptosis too, if the damage is not repairable to activate programmed cell death. CHK1/CHK2 plays a crucial role in the repair of recombination-mediated double-stranded DNA breaks. The other important functions performed by these proteins are the beginning of DNA replication, the stabilization of replication forks, the resolution of replication stress and the coordination of mitosis, even in the absence of exogenous DNA damage. Prexasertib (LY2606368) is a small ATP-competitive selective inhibitor of CHK1 and CHK2. In preclinical studies, prexasertib in monotherapy has shown to induce DNA damage and tumor cells apoptosis. The preclinical data and early clinical studies advocate the use of prexasertib in solid tumors both in monotherapy and in combination with other drugs (antimetabolites, PARP inhibitors and platinum-based chemotherapy). The safety and the efficacy of combination therapies with prexasertib need to be better evaluated in ongoing clinical trials.

Highlights

  • CHK-1 and CHK2 have an important role in DNA damage response.

  • Inhibition of CHK1 may be an attractive therapeutic strategy to improve outcomes for patients with solid tumors

  • Prexasertib is a CHK-1/2 inhibitor.

  • Prexasertib demonstrated efficacy in early clinical trials when combined with other drugs.

  • There is a potential role in combining prexasertib with chemotherapy and immunotherapy.

  • The safety of combination therapy needs to be better investigated.

Keywords

Advanced squamous cell carcinoma (SCC) Checkpoint kinase 1 and 2 CHK inhibitors CHK1 CHK2 LY2606368 Ovarian cancer PARP inhibitors Prexasertib 

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Dai Y, Grant S (2010) New insights into checkpoint kinase 1 in the DNA damage response signaling network. Clin Cancer Res 16:376–383CrossRefGoogle Scholar
  2. 2.
    Zhang Y, Hunter T (2014) Roles of Chk1 in cell biology and cancer therapy. Int J Cancer 134:1013–1023CrossRefGoogle Scholar
  3. 3.
    Jones RM, Peterman E (2012) Replication fork dynamics and DNA damage response. Biochem J 443:13–26CrossRefGoogle Scholar
  4. 4.
    McNeely S, Beckmann R, Bence Lin AK (2014) CHEK again: revisiting the development of CHK1 inhibitors for cancer therapy. Pharmacol Ther 142:1–10CrossRefGoogle Scholar
  5. 5.
    Syljuasen RG, Sorensen CS, Hansen LT (2005) Inhibition of human Chk1 causes increased initiation of DNA replication, phosphorylation of ATR targets, and DNA breakage. Mol Cell Biol 25:3553–3562CrossRefGoogle Scholar
  6. 6.
    Scorah J, McGowan CH (2009) Claspin and Chk1 regulate replication fork stability by different mechanisms. Cell Cycle 8(7):1036–1043CrossRefGoogle Scholar
  7. 7.
    Petermann E, Maya-Mendoza A, Zachos G et al (2006) Chk1 requirement for high global rates of replication fork progression during normal vertebrate S phase. Mol Cell Biol 26(8):3319–3326CrossRefGoogle Scholar
  8. 8.
    Toledo LI, Altmeyer M, Rask MB et al (2013) ATR prohibits replication catastrophe by preventing global exhaustion of RPA. Cell 155:1088–1103CrossRefGoogle Scholar
  9. 9.
    Zannini I, Delia D, Buscemi G (2014) CHK2 kinase in the DNA damage response and beyond. J Mol Cell Biol 6:442–457CrossRefGoogle Scholar
  10. 10.
    Katsan MB, Bartek J (2004) Cell-cycle checkpoints and cancer. Nature 432:316–323CrossRefGoogle Scholar
  11. 11.
    Patil M, Pabla N, Dong Z (2013) Checkpoint kinase 1 in the DNA damage response and cell cycle regulation. J Mol Life Sci 70:4009–4021CrossRefGoogle Scholar
  12. 12.
    King C, Diaz HB, McNeely S (2015) LY2606368 causes replication catastrophe and antitumor effects through CHK1-dependent mechanisms. Mol Cancer Ther 14(9):2004–2013CrossRefGoogle Scholar
  13. 13.
    Otto T, Sicinsk P (2017) Cell cycle proteins as promising targets in cancer therapy. Nat Rev Cancer 17(2):93–115CrossRefGoogle Scholar
  14. 14.
    Zhong B, Maharaj A, Davis A et al (2018) Development and validation of a sensitive LC MS/MS method for the measurement of the checkpoint kinase 1 inhibitor prexasertib and its application in a cerebral microdialysis study. JPBA 156:97–103Google Scholar
  15. 15.
    Thompson R, Eastman A (2013) The cancer therapeutic potential of Chk1 inhibitors: how mechanistic studies impact on clinical trial design. Br J Clin Pharmacol 76:358–369CrossRefGoogle Scholar
  16. 16.
    Brill E, Yokoyama T, Nair J (2017) Prexasertib, a cell cycle checkpoint kinases 1 and 2 inhibitor, increases in vitro toxicity of PARP inhibition by preventing Rad51 foci formation in BRCA wild type high-grade serous ovarian cancer. Oncotarget 8(67):111026–111040CrossRefGoogle Scholar
  17. 17.
    Sen T, Tong P, Stewart CA (2017) CHK1 inhibition in small-cell lung cancer produces single-agent activity in biomarker-defined disease subsets and combination activity with cisplatin or olaparib. Cancer Res 77(14):3870–3884CrossRefGoogle Scholar
  18. 18.
    Cole KP, Groh JMC, Johnson MD et al (2017) Kilogram-scale prexasertib monolactate monohydrate synthesis under continuous-flow CGMP conditions. Science 356(6343):1144–1150CrossRefGoogle Scholar
  19. 19.
    Di Rorà AGL, Iacobucci I et al (2016) Prexasertib, a Chk1/Chk2 inhibitor, increases the effectiveness of conventional therapy in B-/T-cell progenitor acute lymphoblastic leukemia. Oncotarget 7(33):53377–53391Google Scholar
  20. 20.
    Prakash J, Csaba S (2005) Poly(adp-ribose) polymerase and the therapeutic effects of its inhibitors. Nat Rev Drug Discov 4(5):421CrossRefGoogle Scholar
  21. 21.
    Lowery CD, VanWye AB, Dowless M (2017) The checkpoint kinase 1 inhibitor prexasertib induces regression of preclinical models of human neuroblastoma. Clin Cancer Res 23(15):4354–4363CrossRefGoogle Scholar
  22. 22.
    Zeng L, Beggs RR, Cooper TS (2017) Combining Chk1/2 inhibition with cetuximab and radiation enhances in vitro and in vivo cytotoxicity in head and neck squamous cell carcinoma. Mol Cancer Ther 16(4):591–600CrossRefGoogle Scholar
  23. 23.
    Manic G, Signore M, Sistigu A (2018) CHK1-targeted therapy to deplete DNA replication-stressed, p53-deficient, hyperdiploid colorectal cancer stem cells. Gut 67(5):903–917CrossRefGoogle Scholar
  24. 24.
    Haynes B, Murai J, Lee JM (2018) Restored replication fork stabilization, a mechanism of PARP inhibitor resistance, can be overcome by cell cycle checkpoint inhibition. Cancer Treat Rev 71:1–7CrossRefGoogle Scholar
  25. 25.
    Babiker HM, McBride A, Cooke LS, Mahadevan D (2017) Therapeutic potential of investigational CHK-1 inhibitors for the treatment of solid tumors. Expert Opin Investig Drugs 26(9):1063–1072CrossRefGoogle Scholar
  26. 26.
    Infante JR, Hollebecque A, Postel-Vinay S et al (2017) Phase I study of GDC-0425, a checkpoint kinase 1 inhibitor, in combination with gemcitabine in patients with refractory solid tumors. Clin Cancer Res 23(10):2423–2432CrossRefGoogle Scholar
  27. 27.
    Daud AI, Ashworth MT, Strosberg J et al (2015) Phase I dose-escalation trial of checkpoint kinase 1 inhibitor MK-8776 as monotherapy and in combination with gemcitabine in patients with advanced solid tumors. J Clin Oncol 33(9):1060–1066CrossRefGoogle Scholar
  28. 28.
    Thomas BM, Kaufmann SH, Greer JM et al (2011) Phase I dose-escalation study of SCH 900776 in combination with cytarabine (Ara-C) in patients with acute leukemia. Blood 118:1531Google Scholar
  29. 29.
    Seto T, Esaki T, Hirai F et al (2013) Phase I, dose-escalation study of AZD7762 alone and in combination with gemcitabine in Japanese patients with advanced solid tumours. Cancer Chemother Pharmacol 72(3):619–627CrossRefGoogle Scholar
  30. 30.
    Sausville E, Lorusso P, Carducci M et al (2014) Phase I dose-escalation study of AZD7762, a checkpoint kinase inhibitor, in combination with gemcitabine in US patients with advanced solid tumors. Cancer Chemother Pharmacol 73(3):539–549CrossRefGoogle Scholar
  31. 31.
    Calvo E, Braiteh F, Von Hoff D et al (2016) Phase I study of CHK1 inhibitor LY2603618 in combination with gemcitabine in patients with solid tumors. Oncology 91(5):251–260CrossRefGoogle Scholar
  32. 32.
    Scagliotti G, Kang JH, Smith D et al (2016) Phase II evaluation of LY2603618, a first-generation CHK1 inhibitor, in combination with pemetrexed in patients with advanced or metastatic non-small cell lung cancer. Investig New Drugs 34(5):625–635CrossRefGoogle Scholar
  33. 33.
    Hong D, Infante J, Janku F (2016) Phase I study of LY2606368, a checkpoint kinase 1 inhibitor, in patients with advanced cancer. J Clin Oncol 34(15):1764–1771CrossRefGoogle Scholar
  34. 34.
    Hong DS, Moore K, Patel M (2018) Evaluation of prexasertib, a checkpoint kinase 1 inhibitor, in a phase Ib study of patients with squamous cell carcinoma. Clin Cancer Res 24(14):3263–3272CrossRefGoogle Scholar
  35. 35.
    Sørensen CS, Syljuåsen RG (2012) Safeguarding genome integrity: the checkpoint kinases ATR, CHK1 and WEE1 restrain CDK activity during normal DNA replication. Nucleic Acids Res 40:477–486CrossRefGoogle Scholar
  36. 36.
    Thompson R, Montano R, Eastman A (2012) The Mre11 nuclease is critical for the sensitivity of cells to Chk1 inhibition. PLoS One 7:e44021CrossRefGoogle Scholar
  37. 37.
    Lee JM, Nair J, Zimmer A (2018) Prexasertib, a cell cycle checkpoint kinase 1 and 2 inhibitor, in BRCA wild-type recurrent high-grade serous ovarian cancer: a first-in-class proof-of-concept phase 2 study. Lancet Oncol 19(2):207–215CrossRefGoogle Scholar
  38. 38.
    Konstantinopoulos PA, Ceccaldi R, Shapiro GI et al (2015) Homologous recombination deficiency: exploiting the fundamental vulnerability of ovarian cancer. Cancer Discov 5:1137–1154CrossRefGoogle Scholar
  39. 39.
    Patch AM, Christie EL, Etemadmoghadam D et al (2015) Whole-genome characterization of chemoresistant ovarian cancer. Nature 521:489–494CrossRefGoogle Scholar
  40. 40.
    Karst AM, Jones PM, Vena N et al (2014) Cyclin E1 deregulation occurs early in secretory cell transformation to promote formation of fallopian tube-derived high-grade serous ovarian cancers. Cancer Res 74:1141–1152CrossRefGoogle Scholar
  41. 41.
    CLINICALTRIALS.GOV [Internet]. United States (U.S.): National Library of Medicine. [updated 2018 Sept 4]. http://clinicaltrials.gov. Accessed 20 Jan 2019
  42. 42.
    Iwasa S, Yamamoto N, Shitara K et al (2018) A dose-finding study of the checkpoint kinase 1 inhibitor, prexasertib, in Japanese patients with advanced solid tumors. Cancer Sci 109:3216CrossRefGoogle Scholar
  43. 43.
    Laquente B, Lopez-Martin J, Richards D et al (2017) A phase II study to evaluate LY2603618 in combination with gemcitabine in pancreatic cancer patients. BMC Cancer 17(1):137CrossRefGoogle Scholar
  44. 44.
    Bowtell DD, Bohm S, Ahmed AA et al (2015) Rethinking ovarian cancer II: reducing mortality from high-grade serous ovarian cancer. Nat Rev Cancer 15:668–679CrossRefGoogle Scholar
  45. 45.
    Asaoka Y, Ijichi H, Koike K (2015) PD-1 blockade in tumors with mismatch repair deficiency. N Engl J Med 373(20):1979CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Medical Oncology“Sapienza” University of RomeRomeItaly
  2. 2.Medical Oncology Unit APoliclinico Umberto I, ‘Sapienza’ University of RomeRomeItaly
  3. 3.Division of Thoracic OncologyEuropean Institute of OncologyMilanItaly
  4. 4.Division of Medical Oncology 2“Regina Elena” National Cancer InstituteRomeItaly
  5. 5.Department of Medical Oncology Unit APoliclinico Umberto I, ‘Sapienza’ University of RomeRomeItaly
  6. 6.Department of Gynecological and Obstetric Sciences, and Urological SciencesUniversity “Sapienza” of RomeRomeItaly

Personalised recommendations