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Lymphoma

Dual inhibition of CDK4/Rb and PI3K/AKT/mTOR pathways by ON123300 induces synthetic lethality in mantle cell lymphomas

Leukemia volume 30, pages 86–93 (2016)Cite this article

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Abstract

This study describes the characterization of a novel kinase inhibitor, ON123300, which inhibits CDK4/6 (cyclin-dependent kinases 4 and 6) and phosphatidylinositol 3 kinase-δ (PI3K-δ) and exhibits potent activity against mantle cell lymphomas (MCLs) both in vitro and in vivo. We examined the effects of PD0332991 and ON123300 on cell cycle progression, modulation of the retinoblastoma (Rb) and PI3K/AKT pathways, and the induction of apoptosis in MCL cell lines and patient-derived samples. When Granta 519 and Z138C cells were incubated with PD0332991 and ON123300, both compounds were equally efficient in their ability to inhibit the phosphorylation of Rb family proteins. However, only ON123300 inhibited the phosphorylation of proteins associated with the PI3K/AKT pathway. Cells treated with PD0332991 rapidly accumulated in the G0/G1 phase of cell cycle as a function of increasing concentration. Although ON123300-treated cells arrested similarly at lower concentrations, higher concentrations resulted in the induction of apoptosis, which was not observed in PD0332991-treated samples. Mouse xenograft assays also showed a strong inhibition of MCL tumor growth in ON123300-treated animals. Finally, treatment of ibrutinib-sensitive and -resistant patient-derived MCLs with ON123300 also triggered apoptosis and inhibition of the Rb and PI3K/AKT pathways, suggesting that this compound might be an effective agent in MCL, including ibrutinib-resistant forms of the disease.

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References

  1. Weisenburger DD, Sanger WG, Armitage JO, Purtilo DT . Intermediate lymphocytic lymphoma: immunophenotypic and cytogenetic findings. Blood 1987; 69: 1617–1621.

    CAS  PubMed  Google Scholar 

  2. Vandenberghe E, De Wolf-Peeters C, van den Oord J, Wlodarska I, Delabie J, Stul M et al. Translocation (11;14): a cytogenetic anomaly associated with B-cell lymphomas of non-follicle centre cell lineage. J Pathol 1991; 163: 13–18.

    Article  CAS  Google Scholar 

  3. Bosch F, Jares P, Campo E, Lopez-Guillermo A, Piris MA, Villamor N et al. PRAD-1/cyclin D1 gene overexpression in chronic lymphoproliferative disorders: a highly specific marker of mantle cell lymphoma. Blood 1994; 84: 2726–2732.

    CAS  PubMed  Google Scholar 

  4. Dreyling M, Ferrero S, Vogt N, Klapper W, European Mantle Cell Lymphoma N. New paradigms in mantle cell lymphoma: is it time to risk-stratify treatment based on the proliferative signature? Clin Cancer Res 2014; 20: 5194–5206.

    Article  CAS  Google Scholar 

  5. Fry DW, Harvey PJ, Keller PR, Elliott WL, Meade M, Trachet E et al. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther 2004; 3: 1427–1438.

    CAS  Google Scholar 

  6. Leonard JP, LaCasce AS, Smith MR, Noy A, Chirieac LR, Rodig SJ et al. Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma. Blood 2012; 119: 4597–4607.

    Article  CAS  Google Scholar 

  7. Baker SJ, Reddy EP . CDK4: a key player in the cell cycle, development, and cancer. Genes Cancer 2012; 3: 658–669.

    Article  CAS  Google Scholar 

  8. Parekh S . Taking it up a notch in MCL. Blood 2012; 119: 1957–1958.

    Article  CAS  Google Scholar 

  9. Parekh S, Weniger MA, Wiestner A . New molecular targets in mantle cell lymphoma. Semin Cancer Biol 2011; 21: 335–346.

    Article  CAS  Google Scholar 

  10. Castellano E, Downward J . RAS interaction with PI3K: more than just another effector pathway. Genes Cancer 2011; 2: 261–274.

    Article  CAS  Google Scholar 

  11. Davis RE, Ngo VN, Lenz G, Tolar P, Young RM, Romesser PB et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature 2010; 463: 88–92.

    Article  CAS  Google Scholar 

  12. Ramadani F, Bolland DJ, Garcon F, Emery JL, Vanhaesebroeck B, Corcoran AE et al. The PI3K isoforms p110alpha and p110delta are essential for pre-B cell receptor signaling and B cell development. Sci Signal 2010; 3: ra60.

    Article  Google Scholar 

  13. Tabe Y, Jin L, Konopleva M, Shikami M, Kimura S, Andreeff M et al. Class IA PI3K inhibition inhibits cell growth and proliferation in mantle cell lymphoma. Acta Haematol 2014; 131: 59–69.

    Article  CAS  Google Scholar 

  14. Dal Col J, Zancai P, Terrin L, Guidoboni M, Ponzoni M, Pavan A et al. Distinct functional significance of Akt and mTOR constitutive activation in mantle cell lymphoma. Blood 2008; 111: 5142–5151.

    Article  CAS  Google Scholar 

  15. Rudelius M, Pittaluga S, Nishizuka S, Pham TH, Fend F, Jaffe ES et al. Constitutive activation of Akt contributes to the pathogenesis and survival of mantle cell lymphoma. Blood 2006; 108: 1668–1676.

    Article  CAS  Google Scholar 

  16. Wang ML, Rule S, Martin P, Goy A, Auer R, Kahl BS et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med 2013; 369: 507–516.

    Article  CAS  Google Scholar 

  17. Jessen KA, Lannutti BJ . Putative roles for PI3K alpha and delta isoforms in refractory mantle cell lymphoma. Acta Haematol 2014; 131: 218–219.

    Article  Google Scholar 

  18. Blachly JS, Baiocchi RA . Targeting PI3-kinase (PI3K), AKT and mTOR axis in lymphoma. Br J Haematol 2014; 167: 19–32.

    Article  CAS  Google Scholar 

  19. Chiron D, Di Liberto M, Martin P, Huang X, Sharman J, Blecua P et al. Cell-cycle reprogramming for PI3K inhibition overrides a relapse-specific C481S BTK mutation revealed by longitudinal functional genomics in mantle cell lymphoma. Cancer Discov 2014; 4: 1022–1035.

    Article  CAS  Google Scholar 

  20. Chiron D, Martin P, Di Liberto M, Huang X, Ely S, Lannutti BJ et al. Induction of prolonged early G1 arrest by CDK4/CDK6 inhibition reprograms lymphoma cells for durable PI3Kdelta inhibition through PIK3IP1. Cell Cycle 2013; 12: 1892–1900.

    Article  CAS  Google Scholar 

  21. Reddy MV, Akula B, Cosenza SC, Athuluridivakar S, Mallireddigari MR, Pallela VR et al. Discovery of 8-cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrid o[2,3-d]pyrimidine-6-carbonitrile (7x) as a potent inhibitor of cyclin-dependent kinase 4 (CDK4) and AMPK-related kinase 5 (ARK5). J Med Chem 2014; 57: 578–599.

    Article  CAS  Google Scholar 

  22. Kusakai G, Suzuki A, Ogura T, Kaminishi M, Esumi H . Strong association of ARK5 with tumor invasion and metastasis. J Exp Clin Cancer Res 2004; 23: 263–268.

    CAS  PubMed  Google Scholar 

  23. Suzuki A, Lu J, Kusakai G, Kishimoto A, Ogura T, Esumi H . ARK5 is a tumor invasion-associated factor downstream of Akt signaling. Mol Cell Biol 2004; 24: 3526–3535.

    Article  CAS  Google Scholar 

  24. Marzec M, Kasprzycka M, Lai R, Gladden AB, Wlodarski P, Tomczak E et al. Mantle cell lymphoma cells express predominantly cyclin D1a isoform and are highly sensitive to selective inhibition of CDK4 kinase activity. Blood 2006; 108: 1744–1750.

    Article  CAS  Google Scholar 

  25. Andjelkovic M, Maira SM, Cron P, Parker PJ, Hemmings BA . Domain swapping used to investigate the mechanism of protein kinase B regulation by 3-phosphoinositide-dependent protein kinase 1 and Ser473 kinase. Mol Cell Biol 1999; 19: 5061–5072.

    Article  CAS  Google Scholar 

  26. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM . Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005; 307: 1098–1101.

    Article  CAS  Google Scholar 

  27. Peterson RT, Beal PA, Comb MJ, Schreiber SL . FKBP12-rapamycin-associated protein (FRAP) autophosphorylates at serine 2481 under translationally repressive conditions. J Biol Chem 2000; 275: 7416–7423.

    Article  CAS  Google Scholar 

  28. Dufner A, Andjelkovic M, Burgering BM, Hemmings BA, Thomas G . Protein kinase B localization and activation differentially affect S6 kinase 1 activity and eukaryotic translation initiation factor 4E-binding protein 1 phosphorylation. Mol Cell Biol 1999; 19: 4525–4534.

    Article  CAS  Google Scholar 

  29. Choe G, Horvath S, Cloughesy TF, Crosby K, Seligson D, Palotie A et al. Analysis of the phosphatidylinositol 3'-kinase signaling pathway in glioblastoma patients in vivo. Cancer Res 2003; 63: 2742–2746.

    CAS  PubMed  Google Scholar 

  30. Zhang X, Tang N, Hadden TJ, Rishi AK . Akt, FoxO and regulation of apoptosis. Biochim Biophys Acta 2011; 1813: 1978–1986.

    Article  CAS  Google Scholar 

  31. Rahal R, Frick M, Romero R, Korn JM, Kridel R, Chan FC et al. Pharmacological and genomic profiling identifies NF-kappaB-targeted treatment strategies for mantle cell lymphoma. Nat Med 2014; 20: 87–92.

    Article  CAS  Google Scholar 

  32. Shapiro GI . Cyclin-dependent kinase pathways as targets for cancer treatment. J Clin Oncol 2006; 24: 1770–1783.

    Article  CAS  Google Scholar 

  33. Kahl BS, Spurgeon SE, Furman RR, Flinn IW, Coutre SE, Brown JR et al. A phase 1 study of the PI3Kdelta inhibitor idelalisib in patients with relapsed/refractory mantle cell lymphoma (MCL). Blood 2014; 123: 3398–3405.

    Article  CAS  Google Scholar 

  34. Lv H, Zhang X, Sharma J, Reddy MV, Reddy EP, Gallo JM . Integrated pharmacokinetic-driven approach to screen candidate anticancer drugs for brain tumor chemotherapy. AAPS J 2013; 15: 250–257.

    Article  CAS  Google Scholar 

  35. Zhang X, Lv H, Zhou Q, Elkholi R, Chipuk JE, Reddy MV et al. Preclinical pharmacological evaluation of a novel multiple kinase inhibitor, ON123300, in brain tumor models. Mol Cancer Ther 2014; 13: 1105–1116.

    Article  CAS  Google Scholar 

  36. Montserrat E, Bosch F, Lopez-Guillermo A, Graus F, Terol MJ, Campo E et al. CNS involvement in mantle-cell lymphoma. J Clin Oncol 1996; 14: 941–944.

    Article  CAS  Google Scholar 

  37. Iyengar S, Clear A, Bodor C, Maharaj L, Lee A, Calaminici M et al. P110alpha-mediated constitutive PI3K signaling limits the efficacy of p110delta-selective inhibition in mantle cell lymphoma, particularly with multiple relapse. Blood 2013; 121: 2274–2284.

    Article  CAS  Google Scholar 

  38. Ma J, Lu P, Guo A, Cheng S, Zong H, Martin P et al. Characterization of ibrutinib-sensitive and -resistant mantle lymphoma cells. Br J Haematol 2014; 166: 849–861.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Chen Ren for assistance with liquid chromatography/mass spectrometry studies. This work was supported by grants from the NIH (P01CA-130821), NIH (RO1-CA-158209) and Onconova Therapeutics Inc. to EPR.

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Authors and Affiliations

  1. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    S K A Divakar, M V Ramana Reddy, S C Cosenza, S J Baker, B Akula & E Premkumar Reddy

  2. Department of Hematology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    D Perumal, A C Antonelli, J Brody & S Parekh

  3. Department of Structural Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    E Premkumar Reddy

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  1. S K A Divakar
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Correspondence to E Premkumar Reddy.

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Competing interests

EPR is an equity holder, board member and a paid consultant of Onconova Therapeutics Inc. In addition, EPR and MVRR are named inventors on pending and issued patents filed by Temple University. MVRR is a stockholder and paid consultant of Onconova Therapeutics Inc. SCC and SJB are paid consultants of Onconova Therapeutics Inc. The other authors declare no conflict of interest.

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Divakar, S., Ramana Reddy, M., Cosenza, S. et al. Dual inhibition of CDK4/Rb and PI3K/AKT/mTOR pathways by ON123300 induces synthetic lethality in mantle cell lymphomas. Leukemia 30, 86–93 (2016). https://doi.org/10.1038/leu.2015.185

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