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Synthetic lethal combination of CHK1 and WEE1 inhibition for treatment of castration-resistant prostate cancer

Oncogene volume 43, pages 789–803 (2024)Cite this article

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Abstract

WEE1 and CHEK1 (CHK1) kinases are critical regulators of the G2/M cell cycle checkpoint and DNA damage response pathways. The WEE1 inhibitor AZD1775 and the CHK1 inhibitor SRA737 are in clinical trials for various cancers, but have not been thoroughly examined in prostate cancer, particularly castration-resistant (CRPC) and neuroendocrine prostate cancers (NEPC). Our data demonstrated elevated WEE1 and CHK1 expressions in CRPC and NEPC cell lines and patient samples. AZD1775 resulted in rapid and potent cell killing with comparable IC50s across different prostate cancer cell lines, while SRA737 displayed time-dependent progressive cell killing with 10- to 20-fold differences in IC50s. Notably, their combination synergistically reduced the viability of all CRPC cell lines and tumor spheroids in a concentration- and time-dependent manner. Importantly, in a transgenic mouse model of NEPC, both agents alone or in combination suppressed tumor growth, improved overall survival, and reduced the incidence of distant metastases, with SRA737 exhibiting remarkable single agent anticancer activity. Mechanistically, SRA737 synergized with AZD1775 by blocking AZD1775-induced feedback activation of CHK1 in prostate cancer cells, resulting in increased mitotic entry and accumulation of DNA damage. In summary, this preclinical study shows that CHK1 inhibitor SRA737 alone and its combination with AZD1775 offer potential effective treatments for CRPC and NEPC.

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Fig. 1: Analysis of WEE1 and CHK1 expression in prostate cancer cell lines and patient samples, and correlation to overall survival and prognosis.
Fig. 2: Effects of AZD1775 and SRA737 alone on the viability of CRPC and NEPC prostate cancer cell lines.
Fig. 3: Synthetic lethality of WEE1 and CHK1 inhibition in vitro.
Fig. 4: SRA737 synergized with AZD1775 by blocking AZD1775-induced CHK1 activation in prostate cancer cells.
Fig. 5: AZD1775 and SRA737 alone suppressed NEPC tumor growth in TRAMP mice.
Fig. 6: SRA737 and its combination with AZD1775 were more potent at suppressing tumor growth than AZD1775 in TRAMP mice.

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Data availability

The data generated in this study are available in the article and its supplementary files. Raw and derived data supporting the findings of this study, but not listed in detail, are available from the corresponding author upon request. Expression profile data analyzed in this study were obtained from the Cancer Genome Atlas, including the NEPC dataset [17] (all accessible via https://portal.gdc.cancer.gov/), and publicly available data from the SU2C/PCF Dream Team [36].

References

  1. Elbaek CR, Petrosius V, Sorensen CS. WEE1 kinase limits CDK activities to safeguard DNA replication and mitotic entry. Mutat Res. 2020;819-820:111694.

    Article  CAS  PubMed  Google Scholar 

  2. Qiu Z, Oleinick NL, Zhang J. ATR/CHK1 inhibitors and cancer therapy. Radiother Oncol. 2018;126:450–64.

    Article  CAS  PubMed  Google Scholar 

  3. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Ghelli Luserna di Rora A, Cerchione C, Martinelli G, Simonetti G. A WEE1 family business: regulation of mitosis, cancer progression, and therapeutic target. J Hematol Oncol. 2020;13:126.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Mak JP, Man WY, Chow JP, Ma HT, Poon RY. Pharmacological inactivation of CHK1 and WEE1 induces mitotic catastrophe in nasopharyngeal carcinoma cells. Oncotarget. 2015;6:21074–84.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Corella AN, Cabiliza Ordonio MVA, Coleman I, Lucas JM, Kaipainen A, Nguyen HM, et al. Identification of therapeutic vulnerabilities in small-cell neuroendocrine prostate cancer. Clin Cancer Res. 2020;26:1667–77.

    Article  CAS  PubMed  Google Scholar 

  7. Ku BM, Bae YH, Koh J, Sun JM, Lee SH, Ahn JS, et al. Mutational status of TP53 defines the efficacy of Wee1 inhibitor AZD1775 in KRAS-mutant non-small cell lung cancer. Oncotarget. 2017;8:67526–37.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Hirai H, Iwasawa Y, Okada M, Arai T, Nishibata T, Kobayashi 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.

    Article  CAS  PubMed  Google Scholar 

  9. Kolb EA, Houghton PJ, Kurmasheva RT, Mosse YP, Maris JM, Erickson SW, et al. Preclinical evaluation of the combination of AZD1775 and irinotecan against selected pediatric solid tumors: a Pediatric Preclinical Testing Consortium report. Pediatr Blood Cancer. 2020;67:e28098.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Richer AL, Cala JM, O’Brien K, Carson VM, Inge LJ, Whitsett TG. WEE1 kinase inhibitor AZD1775 has preclinical efficacy in LKB1-deficient non-small cell lung cancer. Cancer Res. 2017;77:4663–72.

    Article  CAS  PubMed  Google Scholar 

  11. Matheson CJ, Venkataraman S, Amani V, Harris PS, Backos DS, Donson AM, et al. A WEE1 inhibitor analog of AZD1775 maintains synergy with cisplatin and demonstrates reduced single-agent cytotoxicity in medulloblastoma cells. ACS Chem Biol. 2016;11:921–30.

    Article  CAS  PubMed  Google Scholar 

  12. Patties I, Kallendrusch S, Bohme L, Kendzia E, Oppermann H, Gaunitz F, et al. The Chk1 inhibitor SAR-020106 sensitizes human glioblastoma cells to irradiation, to temozolomide, and to decitabine treatment. J Exp Clin Cancer Res. 2019;38:420.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Doerr F, George J, Schmitt A, Beleggia F, Rehkamper T, Hermann S, et al. Targeting a non-oncogene addiction to the ATR/CHK1 axis for the treatment of small cell lung cancer. Sci Rep. 2017;7:15511.

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  14. Nyquist MD, Corella A, Coleman I, De Sarkar N, Kaipainen A, Ha G, et al. Combined TP53 and RB1 loss promotes prostate cancer resistance to a spectrum of therapeutics and confers vulnerability to replication stress. Cell Rep. 2020;31:107669.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Tai S, Sun Y, Squires JM, Zhang H, Oh WK, Liang CZ, et al. PC3 is a cell line characteristic of prostatic small cell carcinoma. Prostate. 2011;71:1668–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Robinson D, Van Allen EM, Wu YM, Schultz N, Lonigro RJ, Mosquera JM, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161:1215–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Beltran H, Prandi D, Mosquera JM, Benelli M, Puca L, Cyrta J, et al. Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. Nat Med. 2016;22:298–305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kristeleit R, Plummer R, Jones R, Carter L, Blagden S, Sarker D, et al. A phase 1/2 trial of SRA737 (a Chk1 inhibitor) administered orally in patients with advanced cancer. Br J Cancer. 2023;129:38–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Gorecki L, Andrs M, Korabecny J. Clinical candidates targeting the ATR-CHK1-WEE1 axis in cancer. Cancers. 2021;13:795.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Booth L, Roberts J, Poklepovic A, Dent P. The CHK1 inhibitor SRA737 synergizes with PARP1 inhibitors to kill carcinoma cells. Cancer Biol Ther. 2018;19:786–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zhu Y, Liu C, Nadiminty N, Lou W, Tummala R, Evans CP, et al. Inhibition of ABCB1 expression overcomes acquired docetaxel resistance in prostate cancer. Mol Cancer Ther. 2013;12:1829–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Liu C, Lou W, Zhu Y, Nadiminty N, Schwartz CT, Evans CP, et al. Niclosamide inhibits androgen receptor variants expression and overcomes enzalutamide resistance in castration-resistant prostate cancer. Clin Cancer Res. 2014;20:3198–210.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Liu C, Lou W, Zhu Y, Yang JC, Nadiminty N, Gaikwad NW, et al. Intracrine androgens and AKR1C3 activation confer resistance to enzalutamide in prostate cancer. Cancer Res. 2015;75:1413–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Leung-Pineda V, Ryan CE, Piwnica-Worms H. Phosphorylation of Chk1 by ATR is antagonized by a Chk1-regulated protein phosphatase 2A circuit. Mol Cell Biol. 2006;26:7529–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Bukhari AB, Lewis CW, Pearce JJ, Luong D, Chan GK, Gamper AM. Inhibiting Wee1 and ATR kinases produces tumor-selective synthetic lethality and suppresses metastasis. J Clin Invest. 2019;129:1329–44.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Gingrich JR, Barrios RJ, Kattan MW, Nahm HS, Finegold MJ, Greenberg NM. Androgen-independent prostate cancer progression in the TRAMP model. Cancer Res. 1997;57:4687–91.

    CAS  PubMed  Google Scholar 

  27. Deneka AY, Einarson MB, Bennett J, Nikonova AS, Elmekawy M, Zhou Y, et al. Synthetic lethal targeting of mitotic checkpoints in HPV-negative head and neck cancer. Cancers. 2020;12:306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Carrassa L, Chila R, Lupi M, Ricci F, Celenza C, Mazzoletti M, et al. Combined inhibition of Chk1 and Wee1: in vitro synergistic effect translates to tumor growth inhibition in vivo. Cell Cycle. 2012;11:2507–17.

    Article  CAS  PubMed  Google Scholar 

  29. Magnussen GI, Emilsen E, Giller Fleten K, Engesaeter B, Nahse-Kumpf V, Fjaer R, et al. Combined inhibition of the cell cycle related proteins Wee1 and Chk1/2 induces synergistic anti-cancer effect in melanoma. BMC Cancer. 2015;15:462.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Koh SB, Wallez Y, Dunlop CR, Bernaldo de Quiros Fernandez S, Bapiro TE, Richards FM, et al. Mechanistic distinctions between CHK1 and WEE1 inhibition guide the scheduling of triple therapy with gemcitabine. Cancer Res. 2018;78:3054–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Guertin AD, Martin MM, Roberts B, Hurd M, Qu X, Miselis NR, et al. Unique functions of CHK1 and WEE1 underlie synergistic anti-tumor activity upon pharmacologic inhibition. Cancer Cell Int. 2012;12:45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Sausville E, Lorusso P, Carducci M, Carter J, Quinn MF, Malburg L, et al. Phase I dose-escalation study of AZD7762, a checkpoint kinase inhibitor, in combination with gemcitabine in US patients with advanced solid tumors. Cancer Chemother Pharm. 2014;73:539–49.

    Article  CAS  Google Scholar 

  33. Walton MI, Eve PD, Hayes A, Henley AT, Valenti MR, De Haven Brandon AK, et al. The clinical development candidate CCT245737 is an orally active CHK1 inhibitor with preclinical activity in RAS mutant NSCLC and Emicro-MYC driven B-cell lymphoma. Oncotarget. 2016;7:2329–42.

    Article  PubMed  Google Scholar 

  34. Osborne JD, Matthews TP, McHardy T, Proisy N, Cheung KM, Lainchbury M, et al. Multiparameter lead optimization to give an oral checkpoint kinase 1 (CHK1) inhibitor clinical candidate: (R)-5-((4-((Morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)pyr azine-2-carbonitrile (CCT245737). J Med Chem. 2016;59:5221–37.

    Article  CAS  PubMed  Google Scholar 

  35. Jones R, Plummer R, Moreno V, Carter L, Roda D, Garralda E, et al. A phase I/II trial of oral SRA737 (a Chk1 Inhibitor) given in combination with low-dose gemcitabine in patients with advanced cancer. Clin Cancer Res. 2023;29:331–40.

    Article  CAS  PubMed  Google Scholar 

  36. Abida W, Cyrta J, Heller G, Prandi D, Armenia J, Coleman I, et al. Genomic correlates of clinical outcome in advanced prostate cancer. Proc Natl Acad Sci USA. 2019;116:11428–36.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  37. Heagerty PJ, Lumley T, Pepe MS. Time-dependent ROC curves for censored survival data and a diagnostic marker. Biometrics. 2000;56:337–44.

    Article  CAS  PubMed  Google Scholar 

  38. Liu Q, Yin X, Languino LR, Altieri DC. Evaluation of drug combination effect using a Bliss independence dose-response surface model. Stat Biopharm Res. 2018;10:112–22.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Gingrich JR, Barrios RJ, Morton RA, Boyce BF, DeMayo FJ, Finegold MJ, et al. Metastatic prostate cancer in a transgenic mouse. Cancer Res. 1996;56:4096–102.

    CAS  PubMed  Google Scholar 

  40. Roy A, Veroli MV, Prasad S, Wang QJ. Protein kinase D2 modulates cell cycle by stabilizing Aurora A kinase at centrosomes. Mol Cancer Res. 2018;16:1785–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported in part by the National Institutes of Health grant R01CA229431 (Wang). It also used the UPMC Hillman Cancer Center and Tissue and Research Pathology/Pitt Biospecimen Core shared resource which is supported in part by the award P30CA047904.

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Author notes

  1. These authors contributed equally: Yapeng Chao, Yuzhou Chen.

Authors and Affiliations

  1. Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Yapeng Chao, Yuzhou Chen, Wenxiao Zheng, Yu Liu, Jaclyn A. Connelly & Qiming Jane Wang

  2. Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA

    Kathryn Demanelis & Hong Wang

  3. Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh Hillman Cancer Center, Pittsburgh, PA, USA

    Kathryn Demanelis

  4. Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA

    Song Li

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Contributions

QJW conceived and presented the ideas. YaC, YuC, WZ, YL, and JC performed the experiments and conducted data analysis. QJW wrote the manuscript with the support of YaC, YuC, and JC. KD and HW performed the statistical analyses of the animal data, and QJW supervised the project.

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Correspondence to Qiming Jane Wang.

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Chao, Y., Chen, Y., Zheng, W. et al. Synthetic lethal combination of CHK1 and WEE1 inhibition for treatment of castration-resistant prostate cancer. Oncogene 43, 789–803 (2024). https://doi.org/10.1038/s41388-024-02939-z

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