Molecular targets for therapy

MDM2 inhibition: an important step forward in cancer therapy

Abstract

Targeting the interaction between tumor suppressor p53 and the E3 ligase MDM2 represents an attractive treatment approach for cancers with wild-type or functional TP53. Indeed, several small molecules have been developed and evaluated in various malignancies. We provide an overview of MDM2 inhibitors under preclinical and clinical investigation, with a focus on molecules with ongoing clinical trials, as indicated by ClinicalTrials.gov. Because preclinical and clinical exploration of combination strategies is underway, data supporting these combinations are also described. We identified the following molecules for inclusion in this review: RG7112 (RO5045337), idasanutlin (RG7388), AMG-232 (KRT-232), APG-115, BI-907828, CGM097, siremadlin (HDM201), and milademetan (DS-3032b). Information about each MDM2 inhibitor was collected from major congress records and PubMed using the following search terms: each molecule name, “MDM2”and “HDM2.” Only congress records were limited by date (January 1, 2012–March 6, 2020). Special attention was given to available data in hematologic malignancies; however, available safety data in any indication are reported. Overall, targeting MDM2 is a promising treatment strategy, as evidenced by the increasing number of MDM2 inhibitors entering the clinic. Additional clinical investigation is needed to further elucidate the role of MDM2 inhibitors in the treatment of human cancers.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Activation of p53 by MDM2 inhibition.
Fig. 2: Crystal structure of MDM2 and its p53 binding site.
Fig. 3: Potential synergistic pathways with MDM2 inhibitors, based on currently available clinical data.

References

  1. 1.

    Vogelstein B, Lane D, Levine AJ. Surfing the p53 network. Nature. 2000;408:307–10.

    CAS  PubMed  Google Scholar 

  2. 2.

    Joerger AC, Fersht AR. The p53 pathway: origins, inactivation in cancer, and emerging therapeutic approaches. Annu Rev Biochem. 2016;85:375–404.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Vassilev LT. MDM2 inhibitors for cancer therapy. Trends Mol Med. 2007;13:23–31.

    CAS  PubMed  Google Scholar 

  4. 4.

    Levine AJ, Oren M. The first 30 years of p53: growing ever more complex. Nat Rev Cancer. 2009;9:749–58.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Sabapathy K, Lane DP. Therapeutic targeting of p53: all mutants are equal, but some mutants are more equal than others. Nat Rev Clin Oncol. 2018;15:13–30.

    CAS  PubMed  Google Scholar 

  6. 6.

    Liu Y, Chen C, Xu Z, Scuoppo C, Rillahan CD, Gao J, et al. Deletions linked to TP53 loss drive cancer through p53-independent mechanisms. Nature. 2016;531:471–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Kato S, Han SY, Liu W, Otsuka K, Shibata H, Kanamaru R, et al. Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. Proc Natl Acad Sci USA. 2003;100:8424–9.

    CAS  PubMed  Google Scholar 

  8. 8.

    Momand J, Jung D, Wilczynski S, Niland J. The MDM2 gene amplification database. Nucleic Acids Res. 1998;26:3453–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Karni-Schmidt O, Lokshin M, Prives C. The roles of MDM2 and MDMX in cancer. Annu Rev Pathol. 2016;11:617–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Shangary S, Wang S. Small-molecule inhibitors of the MDM2-p53 protein-protein interaction to reactivate p53 function: a novel approach for cancer therapy. Annu Rev Pharmacol Toxicol. 2009;49:223–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Quintás-Cardama A, Hu C, Qutub A, Qiu YH, Zhang X, Post SM, et al. p53 pathway dysfunction is highly prevalent in acute myeloid leukemia independent of TP53 mutational status. Leukemia. 2017;31:1296–305.

    PubMed  Google Scholar 

  12. 12.

    Kussie PH, Gorina S, Marechal V, Elenbaas B, Moreau J, Levine AJ, et al. Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain. Science. 1996;274:948–53.

    CAS  PubMed  Google Scholar 

  13. 13.

    Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science. 2004;303:844–8.

    CAS  PubMed  Google Scholar 

  14. 14.

    Ding Q, Zhang Z, Liu JJ, Jiang N, Zhang J, Ross TM, et al. Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development. J Med Chem. 2013;56:5979–83.

    CAS  PubMed  Google Scholar 

  15. 15.

    Tovar C, Rosinski J, Filipovic Z, Higgins B, Kolinsky K, Hilton H, et al. Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: implications for therapy. Proc Natl Acad Sci USA. 2006;103:1888–93.

    CAS  PubMed  Google Scholar 

  16. 16.

    Kojima K, Konopleva M, Samudio IJ, Shikami M, Cabreira-Hansen M, McQueen T, et al. MDM2 antagonists induce p53-dependent apoptosis in AML: implications for leukemia therapy. Blood. 2005;106:3150–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Vu B, Wovkulich P, Pizzolato G, Lovey A, Ding Q, Jiang N, et al. Discovery of RG7112: a small-molecule MDM2 inhibitor in clinical development. ACS Med Chem Lett. 2013;4:466–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Lu M, Wang X, Li Y, Tripodi J, Mosoyan G, Mascarenhas J, et al. Combination treatment in vitro with nutlin, a small-molecule antagonist of MDM2, and pegylated interferon-α 2a specifically targets JAK2V617F-positive polycythemia vera cells. Blood. 2012;120:3098–105.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Lu M, Xia L, Li Y, Wang X, Hoffman R. The orally bioavailable MDM2 antagonist RG7112 and pegylated interferon α 2a target JAK2V617F-positive progenitor and stem cells. Blood. 2014;124:771–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Higgins B, Tovar C, Glenn K, Walz A, Filipovic Z, Zhang Y-E, et al. Antitumor activity of the MDM2 antagonist RG7388. Mol Cancer Ther. 2013;12 11 Suppl. (abstract B55).

  21. 21.

    Siu LL, Italiano A, Miller WH, Blay JY, Gietema JA, Bang YJ, et al. Phase 1 dose escalation, food effect, and biomarker study of RG7388, a more potent second-generation MDM2 antagonist, in patients (pts) with solid tumors. J Clin Oncol. 2014;32 Suppl 15. (abstract 2535).

  22. 22.

    Higgins B, Glenn K, Walz A, Tovar C, Filipovic Z, Hussain S, et al. Preclinical optimization of MDM2 antagonist scheduling for cancer treatment by using a model-based approach. Clin Cancer Res. 2014;20:3742–52.

    CAS  PubMed  Google Scholar 

  23. 23.

    Sun D, Li Z, Rew Y, Gribble M, Bartberger MD, Beck HP, et al. Discovery of AMG 232, a potent, selective, and orally bioavailable MDM2-p53 inhibitor in clinical development. J Med Chem. 2014;57:1454–72.

    CAS  PubMed  Google Scholar 

  24. 24.

    Canon J, Osgood T, Olson SH, Saiki AY, Robertson R, Yu D, et al. The MDM2 inhibitor AMG 232 demonstrates robust antitumor efficacy and potentiates the activity of p53-inducing cytotoxic agents. Mol Cancer Ther. 2015;14:649–58.

    CAS  PubMed  Google Scholar 

  25. 25.

    Aguilar A, Lu J, Liu L, Du D, Bernard D, McEachern D. et al. Discovery of 4-((3’R,4’S,5’R)-6″-chloro-4’-(3-chloro-2-fluorophenyl)-1’-ethyl-2″-oxodispiro[cyclohexane-1,2’-pyrrolidine-3’,3″-indoline]-5’-carboxamido)bicyclo[2.2.2]octane-1-carboxylic acid (AA-115/APG-115): a potent and orally active murine double minute 2 (MDM2) inhibitor in clinical eevelopment. J Med Chem. 2017;60:2819–39.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Skalniak L, Surmiak E, Holak TA. A therapeutic patent overview of MDM2/X-targeted therapies (2014–2018). Expert Opin Ther Pat. 2019;29:151–70.

    CAS  PubMed  Google Scholar 

  27. 27.

    Rinnenthal J, Rudolph D, Blake S, Gollner A, Wernitznig A, Weyer-Czernilofsky U, et al. BI 907828: a highly potent MDM2 inhibitor with low human dose estimation, designed for high-dose intermittent schedules in the clinic. Cancer Res. 2018;78 13 Suppl. (abstract 4865).

  28. 28.

    Rudolph D, Gollner A, Blake S, Rinnenthal J, Wernitznig A, Weyer-Czernilofsky U, et al. BI 907828: a novel, potent MDM2 inhibitor that is suitable for high-dose intermittent schedules. Cancer Res. 2018;78 13 Suppl. (abstract 4868).

  29. 29.

    Gessier F, Kallen J, Jacoby E, Chène P, Stachyra-Valat T, Ruetz S, et al. Discovery of dihydroisoquinolinone derivatives as novel inhibitors of the p53-MDM2 interaction with a distinct binding mode. Bioorg Med Chem Lett. 2015;25:3621–5.

    CAS  PubMed  Google Scholar 

  30. 30.

    Holzer P, Masuya K, Furet P, Kallen J, Valat-Stachyra T, Ferretti S, et al. Discovery of a dihydroisoquinolinone derivative (NVP-CGM097): a highly potent and selective MDM2 inhibitor undergoing phase 1 clinical trials in p53wt tumors. J Med Chem. 2015;58:6348–58.

    CAS  PubMed  Google Scholar 

  31. 31.

    Townsend EC, DeSouza T, Murakami MA, Montero J, Stevenson K, Christie AL, et al. The MDM2 inhibitor NVP-CGM097 is highly active in a randomized preclinical trial of B-cell acute lymphoblastic leukemia patient derived xenografts. Blood. 2015;126. (abstract 797).

  32. 32.

    Arnhold V, Schmelz K, Proba J, Winkler A, Wünschel J, Toedling J, et al. Reactivating TP53 signaling by the novel MDM2 inhibitor DS-3032b as a therapeutic option for high-risk neuroblastoma. Oncotarget. 2018;9:2304–19.

    PubMed  Google Scholar 

  33. 33.

    Ishizawa J, Nakamaru K, Seki T, Tazaki K, Kojima K, Chachad D, et al. Predictive gene signatures determine tumor sensitivity to MDM2 inhibition. Cancer Res. 2018;78:2721–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Holzer P. Discovery of potent and selective p53-MDM2 protein-protein interaction inhibitors as anticancer drugs. Chimia. 2017;71:716–21.

    CAS  PubMed  Google Scholar 

  35. 35.

    Ferretti S, Rebmann R, Berger M, Santacroce F, Albrecht G, Pollehn K, et al. Insights into the mechanism of action of NVP-HDM201, a differentiated and versatile next-generation small-molecule inhibitor of Mdm2, under evaluation in phase I clinical trials. Cancer Res. 2016;76 14 Suppl. abstract 1224.

  36. 36.

    Jeay S, Chène P, Ferretti S, Furet P, Gruenenfelder B, Guagnano V, et al. NVP-HDM201: cellular and in vivo profile of a novel highly potent and selective PPI inhibitor of p53-Mdm2. Cancer Res. 2016;76 14 Suppl. (abstract 1225).

  37. 37.

    Stachyra-Valat T, Baysang F, D’Alessandro A-C, Dirk E, Furet P, Guagnano V, et al. NVP-HDM201: biochemical and biophysical profile of a novel highly potent and selective PPI inhibitor of p53-Mdm2. Cancer Res. 2016;76 14 Suppl. (abstract 1239).

  38. 38.

    Ray-Coquard I, Blay JY, Italiano A, Le Cesne A, Penel N, Zhi J, et al. Effect of the MDM2 antagonist RG7112 on the P53 pathway in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: an exploratory proof-of-mechanism study. Lancet Oncol. 2012;13:1133–40.

    CAS  PubMed  Google Scholar 

  39. 39.

    Andreeff M, Kelly KR, Yee K, Assouline S, Strair R, Popplewell L, et al. Results of the phase I trial of RG7112, a small-molecule MDM2 antagonist in leukemia. Clin Cancer Res. 2016;22:868–76.

    CAS  PubMed  Google Scholar 

  40. 40.

    Iancu-Rubin C, Mosoyan G, Glenn K, Gordon RE, Nichols GL, Hoffman R. Activation of p53 by the MDM2 inhibitor RG7112 impairs thrombopoiesis. Exp Hematol. 2014;42:e5.

    Google Scholar 

  41. 41.

    Yee K, Martinelli G, Vey N, Dickinson MJ, Seiter K, Assouline S, et al. Phase 1/1b study of RG7388, a potent MDM2 antagonist, in acute myelogenous leukemia (AML) patients (pts). Blood. 2014;124. (abstract 116).

  42. 42.

    Nemunaitis J, Young A, Ejadi S, Miller W, Chen LC, Nichols G, et al. Effects of posaconazole (a strong CYP3A4 inhibitor), two new tablet formulations, and food on the pharmacokinetics of idasanutlin, an MDM2 antagonist, in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2018;81:529–37.

    CAS  PubMed  Google Scholar 

  43. 43.

    Mascarenhas J, Lu M, Kosiorek H, Virtgaym E, Xia L, Sandy L, et al. Oral idasanutlin in patients with polycythemia vera. Blood. 2019;134:525–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Erba HP, Becker PS, Shami PJ, Grunwald MR, Flesher DL, Zhu M, et al. Phase 1b study of the MDM2 inhibitor AMG 232 with or without trametinib in relapsed/refractory acute myeloid leukemia. Blood Adv. 2019;3:1939–49.

    PubMed  PubMed Central  Google Scholar 

  45. 45.

    Gluck WL, Gounder MM, Frank R, Eskens F, Blay JY, Cassier PA, et al. Phase 1 study of the MDM2 inhibitor AMG 232 in patients with advanced P53 wild-type solid tumors or multiple myeloma. Investig New Drugs. 2019. https://doi.org/10.1007/s10637-019-00840-1.

  46. 46.

    Rasco DW, Lakhani NJ, Li Y, Men L, Wang H, Ji J, et al. A phase I study of a novel MDM2 antagonist APG-115 in patients with advanced solid tumors. J Clin Oncol. 2019;37 15 Suppl. (abstract 3126).

  47. 47.

    Bauer S, Demetri G, Jeay S, Dummer R, Guerreiro N, Tan DS, et al. A phase I, open-label, multi-center, dose escalation study of oral NVP-CGM097, a p53/HDM2-protein-protein interaction inhibitor, in adult patients with selected advanced solid tumors. Ann Oncol. 2016;27 Suppl 6:114–35.

    Google Scholar 

  48. 48.

    DiNardo CD, Rosenthal J, Andreeff M, Zernovak O, Kumar P, Gajee R, et al. Phase 1 dose escalation study of MDM2 inhibitor DS-3032b in patients with hematological malignancies—preliminary results. Blood. 2016;128. (abstract 593).

  49. 49.

    Bauer TM, Gounder MM, Weise AM, Schwartz GK, Carvajal RD, Kumar P, et al. A phase 1 study of MDM2 inhibitor DS-3032b in patients with well/de-differentiated liposarcoma (WD/DD LPS), solid tumors (ST) and lymphomas (L). J Clin Oncol. 2018;36 15 Suppl. (abstract 11514).

  50. 50.

    Gounder MM, Bauer TM, Schwartz GK, Masters T, Carvajal RD, Song S, et al. A phase 1 study of the MDM2 inhibitor DS-3032b in patients (pts) with advanced solid tumors and lymphomas. J Clin Oncol. 2016;34 15 Suppl. (abstract 2581).

  51. 51.

    Stein E, Chromik J, DeAngelo DJ, Chatterjee M, Noppeney R, de Vos F, et al. Phase I dose- and regimen-finding study of NVP-HDM201 in pts with advanced TP53 wt acute leukemias. Cancer Res. 2017;77 13 Suppl. (abstract CT152).

  52. 52.

    Hyman DM, Chatterjee M, de Vos F, Lin C-C, Suárez C, Tai D, et al. Optimizing the therapeutic index of HDM2 inhibition: results from a dose- and regimen-finding phase I study of NVP-HDM201 in pts with TP53 wt advanced tumors. Cancer Res. 2017;77 13 Suppl. (abstract CT150).

  53. 53.

    Mahfoudhi E, Lordier L, Marty C, Pan J, Roy A, Roy L, et al. P53 activation inhibits all types of hematopoietic progenitors and all stages of megakaryopoiesis. Oncotarget. 2016;7:31980–92.

    PubMed  PubMed Central  Google Scholar 

  54. 54.

    Pant V, Quintás-Cardama A, Lozano G. The p53 pathway in hematopoiesis: lessons from mouse models, implications for humans. Blood. 2012;120:5118–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Khurana A, Shafer DA. MDM2 antagonists as a novel treatment option for acute myeloid leukemia: perspectives on the therapeutic potential of idasanutlin (RG7388). Onco Targets Ther. 2019;12:2903–10.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Burgess A, Chia KM, Haupt S, Thomas D, Haupt Y, Lim E. Clinical overview of MDM2/X-targeted therapies. Front Oncol. 2016;6:7.

    PubMed  PubMed Central  Google Scholar 

  57. 57.

    Chen L, Rousseau RF, Middleton SA, Nichols GL, Newell DR, Lunec J, et al. Pre-clinical evaluation of the MDM2-p53 antagonist RG7388 alone and in combination with chemotherapy in neuroblastoma. Oncotarget. 2015;6:10207–21.

    PubMed  PubMed Central  Google Scholar 

  58. 58.

    Barbieri E, Mehta P, Chen Z, Zhang L, Slack A, Berg S, et al. MDM2 inhibition sensitizes neuroblastoma to chemotherapy-induced apoptotic cell death. Mol Cancer Ther. 2006;5:2358–65.

    CAS  PubMed  Google Scholar 

  59. 59.

    Martinelli G, Papayannidis C, Yee K, Vey N, Drummond M, Kelly K, et al. Phase 1B results of idasanutlin + cytarabine (Ara-C) in acute myelogenous leukemia (AML) patients (pts). Haematologica. 2016;101 s1. (abstract S504).

  60. 60.

    Montesinos P, Beckermann BM, Catalani O, Esteve J, Gamel K, Konopleva MY, et al. MIRROS: a randomized, placebo-controlled, Phase III trial of cytarabine ± idasanutlin in relapsed or refractory acute myeloid leukemia. Future Oncol. 2020;16:807–15.

    CAS  PubMed  Google Scholar 

  61. 61.

    Kojima K, Konopleva M, Samudio IJ, Schober WD, Bornmann WG, Andreeff M. Concomitant inhibition of MDM2 and Bcl-2 protein function synergistically induce mitochondrial apoptosis in AML. Cell Cycle. 2006;5:2778–86.

    CAS  PubMed  Google Scholar 

  62. 62.

    Carter BZ, Mak PY, Mak DH, Ruvolo VR, Schober W, McQueen T, et al. Synergistic effects of p53 activation via MDM2 inhibition in combination with inhibition of Bcl-2 or Bcr-Abl in CD34+ proliferating and quiescent chronic myeloid leukemia blast crisis cells. Oncotarget. 2015;6:30487–99.

    PubMed  PubMed Central  Google Scholar 

  63. 63.

    Pan R, Ruvolo V, Mu H, Leverson JD, Nichols G, Reed JC, et al. Synthetic lethality of combined Bcl-2 inhibition and p53 activation in AML: mechanisms and superior antileukemic efficacy. Cancer Cell. 2017;32:e746.

    Google Scholar 

  64. 64.

    Hoffman-Luca CG, Ziazadeh D, McEachern D, Zhao Y, Sun W, Debussche L, et al. Elucidation of acquired resistance to Bcl-2 and MDM2 inhibitors in acute leukemia In vitro and in vivo. Clin Cancer Res. 2015;21:2558–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Luo Q, Pan W, Zhou S, Wang G, Yi H, Yang L, et al. A novel BCL-2 inhibitor APG-2575 exerts synthetic lethality with BTK or MDM2-P53 inhibitor in diffuse large B-cell lymphoma. Oncol Res. 2020. https://doi.org/10.3727/096504020X15825405463920.

  66. 66.

    Lehmann C, Friess T, Birzele F, Kiialainen A, Dangl M. Superior anti-tumor activity of the MDM2 antagonist idasanutlin and the Bcl-2 inhibitor venetoclax in p53 wild-type acute myeloid leukemia models. J Hematol Oncol. 2016;9:50.

    PubMed  PubMed Central  Google Scholar 

  67. 67.

    Herting F, Friess T, Umaña P, Steven M, Klein C. The triple combination of the CD20 antibody obinutuzumab with the Bcl-2 inhibitor venetoclax (GDC-199) and the MDM2 inhibitor idasanutlin results in superior efficacy and long term response in wildtype p53 NHL tumor models. Blood. 2016;128. (abstract 4178).

  68. 68.

    Daver NG, Garcia JS, Jonas BA, Kelly KR, Assouline S, Brandwein JM, et al. Updated results from the venetoclax (Ven) in combination with idasanutlin (Idasa) arm of a phase 1b trial in elderly patients (pts) with relapsed or refractory (R/R) AML ineligible for cytotoxic chemotherapy. Blood. 2019;134 Suppl 1. (abstract 229).

  69. 69.

    Herting F, Herter S, Friess T, Muth G, Bacac M, Sulcova J, et al. Antitumour activity of the glycoengineered type II anti-CD20 antibody obinutuzumab (GA101) in combination with the MDM2-selective antagonist idasanutlin (RG7388). Eur J Haematol. 2016;97:461–70.

    CAS  PubMed  Google Scholar 

  70. 70.

    Chiron D, Bellanger C, Papin A, Tessoulin B, Dousset C, Maiga S, et al. Rational targeted therapies to overcome microenvironment-dependent expansion of mantle cell lymphoma. Blood. 2016;128:2808–18.

    CAS  PubMed  Google Scholar 

  71. 71.

    Herting F, Friess T, Umaña P, Middleton S, Klein C. Chemotherapy-free, triple combination of obinutuzumab, venetoclax and idasanutlin: antitumor activity in xenograft models of non-Hodgkin lymphoma. Leuk Lymphoma. 2018;59:1482–5.

    CAS  PubMed  Google Scholar 

  72. 72.

    Kojima K, Konopleva M, Samudio IJ, Ruvolo V, Andreeff M. Mitogen-activated protein kinase kinase inhibition enhances nuclear proapoptotic function of p53 in acute myelogenous leukemia cells. Cancer Res. 2007;67:3210–9.

    CAS  PubMed  Google Scholar 

  73. 73.

    Kojima K, Shimanuki M, Shikami M, Samudio IJ, Ruvolo V, Corn P, et al. The dual PI3 kinase/mTOR inhibitor PI-103 prevents p53 induction by Mdm2 inhibition but enhances p53-mediated mitochondrial apoptosis in p53 wild-type AML. Leukemia. 2008;22:1728–36.

    CAS  PubMed  Google Scholar 

  74. 74.

    Laroche A, Chaire V, Algeo MP, Karanian M, Fourneaux B, Italiano A. MDM2 antagonists synergize with PI3K/mTOR inhibition in well-differentiated/dedifferentiated liposarcomas. Oncotarget. 2017;8:53968–77.

    PubMed  PubMed Central  Google Scholar 

  75. 75.

    Zeng Z, Liu W, Tsao T, Qiu Y, Zhao Y, Samudio I, et al. High-throughput profiling of signaling networks identifies mechanism-based combination therapy to eliminate microenvironmental resistance in acute myeloid leukemia. Haematologica. 2017;102:1537–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Moschos SJ, Sandhu SK, Lewis KD, Sullivan RJ, Johnson DB, Zhang Y, et al. Phase 1 study of the p53-MDM2 inhibitor AMG 232 combined with trametinib plus dabrafenib or trametinib in patients (pts) with TP53 wild type (TP53WT) metastatic cutaneous melanoma (MCM). J Clin Oncol. 2017;35 15 Suppl. (abstract 2575).

  77. 77.

    Andreeff M, Zhang W, Kumar P, Zernovak O, Daver NG, Isoyama T, et al. Synergistic anti-leukemic activity with combination of FLT3 inhibitor quizartinib and MDM2 inhibitor milademetan in FLT3-ITD mutant/p53 wild-type acute myeloid leukemia models. Blood. 2018;132 Suppl 1. (abstract 2720).

  78. 78.

    Canon JR, Osgood T, Saiki AY, Oliner JD. The MDM2 inhibitor AMG 232 causes tumor regression and potentiates the anti-tumor activity of MEK inhibition and DNA-damaging cytotoxic agents in preclinical models of acute myeloid leukemia. Cancer Res. 2016;76 14 Suppl. (abstract 3761).

  79. 79.

    Zhang W, Konopleva M, Burks JK, Dywer KC, Schober WD, Yang JY, et al. Blockade of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase and murine double minute synergistically induces apoptosis in acute myeloid leukemia via BH3-only proteins Puma and Bim. Cancer Res. 2010;70:2424–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Saiki AY, Caenepeel S, Yu D, Lofgren JA, Osgood T, Robertson R, et al. MDM2 antagonists synergize broadly and robustly with compounds targeting fundamental oncogenic signaling pathways. Oncotarget. 2014;5:2030–43.

    PubMed  PubMed Central  Google Scholar 

  81. 81.

    Wang HQ, Zubrowski M, Emerson E, Pradhan E, Jeay S, Wiesmann M, et al. The Mdm2 inhibitor, NVP-CGM097, in combination with the BRAF inhibitor NVP-LGX818 elicits synergistic antitumor effects in melanoma. Cancer Res. 2014;74 19 Suppl. (abstract 5466).

  82. 82.

    Lu M, Zhang W, Li Y, Berenzon D, Wang X, Wang J, et al. Interferon-α targets JAK2V617F-positive hematopoietic progenitor cells and acts through the p38 MAPK pathway. Exp Hematol. 2010;38:472–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Dembla V, Somaiah N, Barata P, Hess K, Fu S, Janku F, et al. Prevalence of MDM2 amplification and coalterations in 523 advanced cancer patients in the MD Anderson phase 1 clinic. Oncotarget. 2018;9:33232–43.

    PubMed  PubMed Central  Google Scholar 

  84. 84.

    Razak AA, Bauer S, Blay J-Y, Quek R, Suárez C, Lin C-C, et al. Results of a dose- and regimen-finding phase Ib study of HDM201 in combination with ribociclib in patients with locally advanced or metastatic liposarcoma. Cancer Res. 2018;78 13 Suppl. (abstract CT009).

  85. 85.

    Laroche-Clary A, Chaire V, Algeo MP, Derieppe MA, Loarer FL, Italiano A. Combined targeting of MDM2 and CDK4 is synergistic in dedifferentiated liposarcomas. J Hematol Oncol. 2017;10:123.

    PubMed  PubMed Central  Google Scholar 

  86. 86.

    Sriraman A, Dickmanns A, Najafova Z, Johnsen SA, Dobbelstein M. CDK4 inhibition diminishes p53 activation by MDM2 antagonists. Cell Death Dis. 2018;9:918.

    PubMed  PubMed Central  Google Scholar 

  87. 87.

    Kato S, Goodman A, Walavalkar V, Barkauskas DA, Sharabi A, Kurzrock R. Hyperprogressors after immunotherapy: analysis of genomic alterations associated with accelerated growth rate. Clin Cancer Res. 2017;23:4242–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Hou H, Sun D, Zhang X. The role of MDM2 amplification and overexpression in therapeutic resistance of malignant tumors. Cancer Cell Int. 2019;19:216.

    PubMed  PubMed Central  Google Scholar 

  89. 89.

    Wang HQ, Liang J, Mulford I, Sharp F, Gaulis S, Chen Y, et al. PD-1/PD-L1 blockade enhances MDM2 inhibitor activity in p53 wild-type cancers. Cancer Res. 2018;78 13 Suppl. (abstract 5560).

  90. 90.

    Rudolph D, Reschke M, Blake S, Rinnenthal J, Wernitznig A, Weyer-Czernilofsky U, et al. BI 907828: A novel, potent MDM2 inhibitor that induces antitumor immunologic memory and acts synergistically with an anti-PD-1 antibody in syngeneic mouse models of cancer. Cancer Res. 2018;78 13 Suppl. (abstract 4866).

  91. 91.

    Fang DD, Tang Q, Kong Y, Wang Q, Gu J, Fang X, et al. MDM2 inhibitor APG-115 synergizes with PD-1 blockade through enhancing antitumor immunity in the tumor microenvironment. J Immunother Cancer. 2019;7:327.

    PubMed  PubMed Central  Google Scholar 

  92. 92.

    Tolcher AW, Karim R, Tang Y, Ji J, Wang H, Meng L, et al. Phase Ib study of a novel MDM2 inhibitor APG-115, in combination with pembrolizumab in patients with metastatic solid tumors in U.S. Mol Cancer Ther. 2019;18 Suppl 12. (abstract A086).

  93. 93.

    Carita G, Frisch-Dit-Leitz E, Dahmani A, Raymondie C, Cassoux N, Piperno-Neumann S, et al. Dual inhibition of protein kinase C and p53-MDM2 or PKC and mTORC1 are novel efficient therapeutic approaches for uveal melanoma. Oncotarget. 2016;7:33542–56.

    PubMed  PubMed Central  Google Scholar 

  94. 94.

    Yi H-J, Yan X-L, Luo Q-Y, Yuan L, Li B, Pan W, et al. A novel MDM2-p53 antagonist APG-115 induces p53-mediated apoptosis and enhances radiosensitivity in colorectal cancer. Cancer Res. 2018;78 13 Suppl. (abstract 314).

  95. 95.

    Houghton PJ, Phelps DA, Bondra K, Seum S, Chronowski C, Leasure J, et al. Inhibition of MDM2 by RG7388 confers hypersensitivity to X-radiation in xenograft models of childhood sarcoma. Cancer Res. 2015;75 15 Suppl. (abstract 1614).

  96. 96.

    Werner LR, Huang S, Francis DM, Armstrong EA, Ma F, Li C, et al. Small molecule inhibition of MDM2-p53 interaction augments radiation response in human tumors. Mol Cancer Ther. 2015;14:1994–2003.

    CAS  PubMed  Google Scholar 

  97. 97.

    Berberich A, Kessler T, Thome CM, Pusch S, Hielscher T, Sahm F, et al. Targeting resistance against the MDM2 inhibitor RG7388 in glioblastoma cells by the MEK inhibitor trametinib. Clin Cancer Res. 2019;25:253–65.

    CAS  PubMed  Google Scholar 

  98. 98.

    Xu Welliver M, Van Tine BA, Houghton P, Rudek MA, Pollock RE, Kane JM, et al. MDM2 inhibitor AMG-232 and radiation therapy in treating patients with soft tissue sarcoma with wild-type TP53: a phase IB study (NRG-DT001). J Clin Oncol. 2019;37 15 Suppl. (abstract TPS11076).

  99. 99.

    Eran Z, Zingariello M, Bochicchio MT, Bardelli C, Migliaccio AR. Novel strategies for the treatment of myelofibrosis driven by recent advances in understanding the role of the microenvironment in its etiology. F1000Res. 2019;8:1662.

    Google Scholar 

  100. 100.

    Jeay S, Berghausen J, Buschmann N, Chène P, Cozens R, Erdmann D, et al. Discovery of NVP-CGM097, a highly potent and optimized small molecule inhibitor of Mdm2 under evaluation in a phase I clinical trial. Cancer Res. 2014;74 19 Suppl. (abstract 1797).

Download references

Acknowledgements

Supported by F. Hoffmann-La Roche Ltd. Support for third-party writing assistance for this paper—by Kia C. E. Walcott, Ph.D., of Health Interactions, Inc.—was provided by F. Hoffmann-La Roche, Ltd.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Marina Konopleva.

Ethics declarations

Conflict of interest

MK has received research support and advisory or consultancy fees from Roche/Genentech and AbbVie. GM has no conflict of interests to disclose. ND has received grants and personal fees from Genentech, Pfizer, AbbVie, Astellas, Bristol Myers Squibb, Agios, Immunogen, Servier, and Daiichi Sankyo; grants from Novimmune; and personal fees from Jazz. CP has no conflict of interests to disclose. AW has received honoraria from and held consulting or advisory roles for Novartis, Astellas, Pfizer, MacroGenics, AbbVie, Genentech, Servier, Celgene, Amgen, AstraZeneca, and Janssen; been part of the speakers bureau for AbbVie, Genentech and Novartis; received research funding from Novartis, Celgene, AbbVie, Servier, AstraZeneca and Amgen; and is a former employee of the Walter and Eliza Hall Institute and receives a part of their royalty stream related to venetoclax. BH is a full-time employee of Roche and owns stock in the company. MO is a full-time employee of Roche and owns stock in the company. JM has received grants and personal fees from Roche, Incyte, Promedior, PharmaEssentia; grants from Kartos, Novartis, Merck, CTI Biopharma, and Janssen; and personal fees from Celgene and AbbVie. MA has received research support from Daiichi Sankyo.

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

Verify currency and authenticity via CrossMark

Cite this article

Konopleva, M., Martinelli, G., Daver, N. et al. MDM2 inhibition: an important step forward in cancer therapy. Leukemia (2020). https://doi.org/10.1038/s41375-020-0949-z

Download citation