CHK1 plays a critical role in the anti-leukemic activity of the wee1 inhibitor MK-1775 in acute myeloid leukemia cells

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• 作者：Wenxiu Qi (1)
  Chengzhi Xie (1) (2) (3)
  Chunhuai Li (4)
  J Timothy Caldwell (5) (6)
  Holly Edwards (2) (3)
  Jeffrey W Taub (3) (7) (8)
  Yue Wang (4)
  Hai Lin (9)
  Yubin Ge (1) (2) (3)
  
  1. National Engineering Laboratory for AIDS Vaccine ; Key Laboratory for Molecular Enzymology & Engineering ; the Ministry of Education ; and School of Life Sciences ; Jilin University ; Changchun ; China
  2. Department of Oncology ; Wayne State University School of Medicine ; 110 East Warren Ave ; 48201 ; Detroit ; MI ; USA
  3. Molecular Therapeutics Program ; Barbara Ann Karmanos Cancer Institute ; Wayne State University School of Medicine ; 110 East Warren Ave ; Detroit ; MI ; USA
  4. Department of Pediatric Hematology and Oncology ; The First Hospital of Jilin University ; Changchun ; China
  5. MD/PhD Program ; Wayne State University School of Medicine ; 540 E. Canfield Ave ; Detroit ; MI ; USA
  6. Cancer Biology Program ; Wayne State University School of Medicine ; 110 East Warren Ave ; Detroit ; MI ; USA
  7. Department of Pediatrics ; Wayne State University School of Medicine ; 540 E. Canfield Ave ; Detroit ; MI ; USA
  8. Division of Pediatric Hematology/Oncology ; Children鈥檚 Hospital of Michigan ; 3901 Beaubien Blvd ; Detroit ; MI ; USA
  9. Department of Hematology and Oncology ; The First Hospital of Jilin University ; Changchun ; China
  
• 关键词：Wee1 ; MK ; 1775 ; CHK1 ; Acute myeloid leukemia
• 刊名：Journal of Hematology & Oncology
• 出版年：2014
• 出版时间：December 2014
• 年：2014
• 卷：7
• 期：1
• 全文大小：2,032 KB
• 参考文献：1. Siegel, R, Naishadham, D, Jemal, A (2013) Cancer statistics, 2013. CA Cancer J Clin 63: pp. 11-30 CrossRef
  2. Rubnitz, JE, Inaba, H, Dahl, G, Ribeiro, RC, Bowman, WP, Taub, J, Pounds, S, Razzouk, BI, Lacayo, NJ, Cao, X, Meshinchi, S, Degar, B, Airewele, G, Raimondi, SC, Onciu, M, Coustan-Smith, E, Downing, JR, Leung, W, Pui, CH, Campana, D (2010) Minimal residual disease-directed therapy for childhood acute myeloid leukaemia: results of the AML02 multicentre trial. The lancet oncology 11: pp. 543-552 70-2045(10)70090-5" target="_blank" title="It opens in new window">CrossRef
  3. Helleday, T, Petermann, E, Lundin, C, Hodgson, B, Sharma, RA (2008) DNA repair pathways as targets for cancer therapy. Nat Rev Cancer 8: pp. 193-204 CrossRef
  4. Parker, LL, Piwnica-Worms, H (1992) Inactivation of the p34cdc2-cyclin B complex by the human WEE1 tyrosine kinase. Science 257: pp. 1955-1957 CrossRef
  5. Watanabe, N, Broome, M, Hunter, T (1995) Regulation of the human WEE1Hu CDK tyrosine 15-kinase during the cell cycle. EMBO J 14: pp. 1878-1891
  6. Peng, CY, Graves, PR, Thoma, RS, Wu, Z, Shaw, AS, Piwnica-Worms, H (1997) Mitotic and G2 checkpoint control: regulation of 14-3-3 protein binding by phosphorylation of Cdc25C on serine-216. Science 277: pp. 1501-1505 77.5331.1501" target="_blank" title="It opens in new window">CrossRef
  7. Sanchez, Y, Wong, C, Thoma, RS, Richman, R, Wu, Z, Piwnica-Worms, H, Elledge, SJ (1997) Conservation of the Chk1 checkpoint pathway in mammals: linkage of DNA damage to Cdk regulation through Cdc25. Science 277: pp. 1497-1501 77.5331.1497" target="_blank" title="It opens in new window">CrossRef
  8. Liu, Q, Guntuku, S, Cui, XS, Matsuoka, S, Cortez, D, Tamai, K, Luo, G, Carattini-Rivera, S, DeMayo, F, Bradley, A, Donehower, LA, Elledge, SJ (2000) Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint. Genes Dev 14: pp. 1448-1459 CrossRef
  9. Zhao, H, Piwnica-Worms, H (2001) ATR-mediated checkpoint pathways regulate phosphorylation and activation of human Chk1. Mol Cell Biol 21: pp. 4129-4139 CrossRef
  10. Hirai, H, Iwasawa, Y, Okada, M, Arai, T, Nishibata, T, Kobayashi, M, Kimura, T, Kaneko, N, Ohtani, J, Yamanaka, K, Itadani, H, Takahashi-Suzuki, I, Fukasawa, K, Oki, H, Nambu, T, Jiang, J, Sakai, T, Arakawa, H, Sakamoto, T, Sagara, T, Yoshizumi, T, Mizuarai, S, Kotani, H (2009) Small-molecule inhibition of Wee1 kinase by MK-1775 selectively sensitizes p53-deficient tumor cells to DNA-damaging agents. Mol Cancer Ther 8: pp. 2992-3000 7163.MCT-09-0463" target="_blank" title="It opens in new window">CrossRef
  11. Aarts, M, Sharpe, R, Garcia-Murillas, I, Gevensleben, H, Hurd, MS, Shumway, SD, Toniatti, C, Ashworth, A, Turner, NC (2012) Forced mitotic entry of S-phase cells as a therapeutic strategy induced by inhibition of WEE1. Cancer Discov 2: pp. 524-539 CrossRef
  12. Bridges, KA, Hirai, H, Buser, CA, Brooks, C, Liu, H, Buchholz, TA, Molkentine, JM, Mason, KA, Meyn, RE (2011) MK-1775, a novel Wee1 kinase inhibitor, radiosensitizes p53-defective human tumor cells. Clin Cancer Res 17: pp. 5638-5648 78-0432.CCR-11-0650" target="_blank" title="It opens in new window">CrossRef
  13. Chaudhuri, L, Vincelette, ND, Koh, BD, Naylor, RM, Flatten, KS, Peterson, KL, McNally, A, Gojo, I, Karp, JE, Mesa, RA, Sproat, LO, Bogenberger, JM, Kaufmann, SH, Tibes, R (2014) CHK1 and WEE1 inhibition combine synergistically to enhance therapeutic efficacy in acute myeloid leukemia ex vivo. Haematologica 99: pp. 688-696 7" target="_blank" title="It opens in new window">CrossRef
  14. Guertin, AD, Li, J, Liu, Y, Hurd, MS, Schuller, AG, Long, B, Hirsch, HA, Feldman, I, Benita, Y, Toniatti, C, Zawel, L, Fawell, SE, Gilliland, DG, Shumway, SD (2013) Preclinical evaluation of the WEE1 inhibitor MK-1775 as single-agent anticancer therapy. Mol Cancer Ther 12: pp. 1442-1452 7163.MCT-13-0025" target="_blank" title="It opens in new window">CrossRef
  15. Hirai, H, Arai, T, Okada, M, Nishibata, T, Kobayashi, M, Sakai, N, Imagaki, K, Ohtani, J, Sakai, T, Yoshizumi, T, Mizuarai, S, Iwasawa, Y, Kotani, H (2010) MK-1775, a small molecule Wee1 inhibitor, enhances anti-tumor efficacy of various DNA-damaging agents, including 5-fluorouracil. Cancer Biol Ther 9: pp. 514-522 7.11115" target="_blank" title="It opens in new window">CrossRef
  16. Kuendgen, A, Schmid, M, Schlenk, R, Knipp, S, Hildebrandt, B, Steidl, C, Germing, U, Haas, R, Dohner, H, Gattermann, N (2006) The histone deacetylase (HDAC) inhibitor valproic acid as monotherapy or in combination with all-trans retinoic acid in patients with acute myeloid leukemia. Cancer 106: pp. 112-119 CrossRef
  17. Rajeshkumar, NV, Oliveira, E, Ottenhof, N, Watters, J, Brooks, D, Demuth, T, Shumway, SD, Mizuarai, S, Hirai, H, Maitra, A, Hidalgo, M (2011) MK-1775, a potent Wee1 inhibitor, synergizes with gemcitabine to achieve tumor regressions, selectively in p53-deficient pancreatic cancer xenografts. Clin Cancer Res 17: pp. 2799-2806 78-0432.CCR-10-2580" target="_blank" title="It opens in new window">CrossRef
  18. Linden, AA, Baturin, D, Ford, JB, Fosmire, SP, Gardner, L, Korch, C, Reigan, P, Porter, CC (2013) Inhibition of Wee1 Sensitizes Cancer Cells to Antimetabolite Chemotherapeutics In Vitro and In Vivo, Independent of p53 Functionality. Mol Cancer Ther 12: pp. 2675-2684 7163.MCT-13-0424" target="_blank" title="It opens in new window">CrossRef
  19. Krajewska, M, Heijink, AM, Bisselink, YJ, Seinstra, RI, Sillje, HH, Vries, EG, Vugt, MA (2013) Forced activation of Cdk1 via wee1 inhibition impairs homologous recombination. Oncogene 32: pp. 3001-3008 CrossRef
  20. Redon, CE, Nakamura, AJ, Zhang, YW, Ji, JJ, Bonner, WM, Kinders, RJ, Parchment, RE, Doroshow, JH, Pommier, Y (2010) Histone gammaH2AX and poly(ADP-ribose) as clinical pharmacodynamic biomarkers. Clin Cancer Res 16: pp. 4532-4542 78-0432.CCR-10-0523" target="_blank" title="It opens in new window">CrossRef
  21. Grignani, F, Ferrucci, PF, Testa, U, Talamo, G, Fagioli, M, Alcalay, M, Mencarelli, A, Grignani, F, Peschle, C, Nicoletti, I, Pelicci, PG (1993) The acute promyelocytic leukemia-specific PML-RAR alpha fusion protein inhibits differentiation and promotes survival of myeloid precursor cells. Cell 74: pp. 423-431 74(93)80044-F" target="_blank" title="It opens in new window">CrossRef
  22. Lin, RJ, Sternsdorf, T, Tini, M, Evans, RM (2001) Transcriptional regulation in acute promyelocytic leukemia. Oncogene 20: pp. 7204-7215 CrossRef
  23. Hoemme, C, Peerzada, A, Behre, G, Wang, Y, McClelland, M, Nieselt, K, Zschunke, M, Disselhoff, C, Agrawal, S, Isken, F, Tidow, N, Berdel, WE, Serve, H, Muller-Tidow, C (2008) Chromatin modifications induced by PML-RARalpha repress critical targets in leukemogenesis as analyzed by ChIP-Chip. Blood 111: pp. 2887-2895 7-03-079921" target="_blank" title="It opens in new window">CrossRef
  24. Russell, MR, Levin, K, Rader, J, Belcastro, L, Li, Y, Martinez, D, Pawel, B, Shumway, SD, Maris, JM, Cole, KA (2013) Combination therapy targeting the Chk1 and Wee1 kinases shows therapeutic efficacy in neuroblastoma. Cancer Res 73: pp. 776-784 72.CAN-12-2669" target="_blank" title="It opens in new window">CrossRef
  25. Carrassa, L, Chila, R, Lupi, M, Ricci, F, Celenza, C, Mazzoletti, M, Broggini, M, Damia, G (2012) Combined inhibition of Chk1 and Wee1: in vitro synergistic effect translates to tumor growth inhibition in vivo. Cell Cycle 11: pp. 2507-2517 CrossRef
  26. Davies, KD, Cable, PL, Garrus, JE, Sullivan, FX, Carlowitz, I, Huerou, YL, Wallace, E, Woessner, RD, Gross, S (2011) Chk1 inhibition and Wee1 inhibition combine synergistically to impede cellular proliferation. Cancer Biol Ther 12: pp. 788-796 7673" target="_blank" title="It opens in new window">CrossRef
  27. Taub, JW, Matherly, LH, Stout, ML, Buck, SA, Gurney, JG, Ravindranath, Y (1996) Enhanced metabolism of 1-beta-D-arabinofuranosylcytosine in Down syndrome cells: a contributing factor to the superior event free survival of Down syndrome children with acute myeloid leukemia. Blood 87: pp. 3395-3403
  28. Niu, X, Wang, G, Wang, Y, Caldwell, JT, Edwards, H, Xie, C, Taub, JW, Li, C, Lin, H, Ge, Y (2014) Acute myeloid leukemia cells harboring MLL fusion genes or with the acute promyelocytic leukemia phenotype are sensitive to the Bcl-2-selective inhibitor ABT-199. Leukemia 28: pp. 1557-1560 72" target="_blank" title="It opens in new window">CrossRef
  29. Xie, C, Edwards, H, Xu, X, Zhou, H, Buck, SA, Stout, ML, Yu, Q, Rubnitz, JE, Matherly, LH, Taub, JW, Ge, Y (2010) Mechanisms of synergistic antileukemic interactions between valproic acid and cytarabine in pediatric acute myeloid leukemia. Clin Cancer Res 16: pp. 5499-5510 78-0432.CCR-10-1707" target="_blank" title="It opens in new window">CrossRef
  30. Xu, X, Xie, C, Edwards, H, Zhou, H, Buck, SA, Ge, Y (2011) Inhibition of histone deacetylases 1 and 6 enhances cytarabine-induced apoptosis in pediatric acute myeloid leukemia cells. PLoS One 6: pp. e17138 71/journal.pone.0017138" target="_blank" title="It opens in new window">CrossRef
  31. Ge, Y, Dombkowski, AA, LaFiura, KM, Tatman, D, Yedidi, RS, Stout, ML, Buck, SA, Massey, G, Becton, DL, Weinstein, HJ, Ravindranath, Y, Matherly, LH, Taub, JW (2006) Differential gene expression, GATA1 target genes, and the chemotherapy sensitivity of Down syndrome megakaryocytic leukemia. Blood 107: pp. 1570-1581 CrossRef
  32. Ge, Y, Stout, ML, Tatman, DA, Jensen, TL, Buck, S, Thomas, RL, Ravindranath, Y, Matherly, LH, Taub, JW (2005) GATA1, cytidine deaminase, and the high cure rate of Down syndrome children with acute megakaryocytic leukemia. J Natl Cancer Inst 97: pp. 226-231 CrossRef
  33. Edwards, H, Xie, C, LaFiura, KM, Dombkowski, AA, Buck, SA, Boerner, JL, Taub, JW, Matherly, LH, Ge, Y (2009) RUNX1 regulates phosphoinositide 3-kinase/AKT pathway: role in chemotherapy sensitivity in acute megakaryocytic leukemia. Blood 114: pp. 2744-2752 79812" target="_blank" title="It opens in new window">CrossRef
  34. Wang, G, He, J, Zhao, J, Yun, W, Xie, C, Taub, JW, Azmi, A, Mohammad, RM, Dong, Y, Kong, W, Guo, Y, Ge, Y (2012) Class I and class II histone deacetylases are potential therapeutic targets for treating pancreatic cancer. PloS One 7: pp. e52095 71/journal.pone.0052095" target="_blank" title="It opens in new window">CrossRef
  
• 刊物主题：Oncology; Hematology; Cancer Research;
• 出版者：BioMed Central
• ISSN：1756-8722

文摘

Background Acute myeloid leukemia (AML) remains a difficult disease to treat and requires new therapies to improve treatment outcome. Wee1 inhibitors have been used to prevent activation of the G2 cell cycle checkpoint, thus enhancing the antitumor activity of DNA damaging agents. In this study, we investigated MK-1775 in AML cell lines and diagnostic blast samples to identify sensitive subtypes as well as possible mechanisms of resistance. Methods In vitro MK-1775 cytotoxicities of AML cell lines and diagnostic blasts were measured using MTT assays. The effects of MK-1775 on cell cycle progression and related proteins were determined by propidium iodide (PI) staining and flow cytometry analysis and Western blotting. Drug-induced apoptosis was determined using annexin V/PI staining and flow cytometry analysis. Results We found that newly diagnosed and relapsed patient samples were equally sensitive to MK-1775. In addition, patient samples harboring t(15;17) translocation were significantly more sensitive to MK-1775 than non-t(15;17) samples. MK-1775 induced apoptosis in both AML cell lines and diagnostic blast samples, accompanied by decreased phosphorylation of CDK1 and CDK2 on Tyr-15 and increased DNA double-strand breaks (DSBs). Time-course experiments, using AML cell lines, revealed a time-dependent increase in DNA DSBs, activation of CHK1 and subsequent apoptosis following MK-1775 treatment, which could be attenuated by a CDK1/2 inhibitor, Roscovitine. Simultaneous inhibition of CHK1 and Wee1 resulted in synergistic anti-leukemic activity in both AML cell lines and primary patient samples ex vivo. Conclusions Our study provides compelling evidence that CHK1 plays a critical role in the anti-leukemic activity of MK-1775 and highlights a possible mechanism of resistance to MK-1775. In addition, our study strongly supports the use of MK-1775 to treat both newly diagnosed and relapsed AML, especially cases with t(15;17) translocation, and supports the development of combination therapies with CHK1 inhibitors.