Targeting p53-MDM2 Interaction Using Small Molecule Inhibitors and the Challenges Needed to be Addressed

Author(s): Maryam Zanjirband* , Soheila Rahgozar .

Journal Name: Current Drug Targets

Volume 20 , Issue 11 , 2019

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Graphical Abstract:


Abstract:

MDM2 protein is the core negative regulator of p53 that maintains the cellular levels of p53 at a low level in normal cells. Mutation of the TP53 gene accounts for 50% of all human cancers. In the remaining malignancies with wild-type TP53, p53 function is inhibited through other mechanisms. Recently, synthetic small molecule inhibitors have been developed which target a small hydrophobic pocket on MDM2 to which p53 normally binds. Given that MDM2-p53 antagonists have been undergoing clinical trials for different types of cancer, this review illustrates different aspects of these new cancer targeted therapeutic agents with the focus on the major advances in the field. It emphasizes on the p53 function, regulation of p53, targeting of the p53-MDM2 interaction for cancer therapy, and p53-dependent and -independent effects of inhibition of p53-MDM2 interaction. Then, representatives of small molecule MDM2-p53 binding antagonists are introduced with a focus on those entered into clinical trials. Furthermore, the review discusses the gene signatures in order to predict sensitivity to MDM2 antagonists, potential side effects and the reasons for the observed hematotoxicity, mechanisms of resistance to these drugs, their evaluation as monotherapy or in combination with conventional chemotherapy or with other targeted therapeutic agents. Finally, it highlights the certainly intriguing questions and challenges which would be addressed in future studies.

Keywords: MDM2, p53, MDM2-p53 antagonists, p53-independent effects, gene signature, hematotoxicity.

[1]
Baudino TA. Targeted cancer therapy: The next generation of cancer treatment. Curr Drug Discov Technol 2015; 12(1): 3-20.
[http://dx.doi.org/10.2174/1570163812666150602144310] [PMID: 26033233]
[2]
Khoo KH, Verma CS, Lane DP. Drugging the p53 pathway: Understanding the route to clinical efficacy. Nat Rev Drug Discov 2014; 13(3): 217-36.
[http://dx.doi.org/10.1038/nrd4236] [PMID: 24577402]
[3]
Duffy MJ, Synnott NC, Crown J. Mutant p53 as a target for cancer treatment. Eur J Cancer 2017; 83: 258-65.
[http://dx.doi.org/10.1016/j.ejca.2017.06.023] [PMID: 28756138]
[4]
Sun D, Li Z, Rew Y, et al. Discovery of AMG 232, a potent, selective, and orally bioavailable MDM2-p53 inhibitor in clinical development. J Med Chem 2014; 57(4): 1454-72.
[http://dx.doi.org/10.1021/jm401753e] [PMID: 24456472]
[5]
Arkin MR, Tang Y, Wells JA. Small-molecule inhibitors of protein-protein interactions: Progressing toward the reality. Chem Biol 2014; 21(9): 1102-14.
[http://dx.doi.org/10.1016/j.chembiol.2014.09.001] [PMID: 25237857]
[6]
Burgess A, Chia KM, Haupt S, Thomas D, Haupt Y, Lim E. Clinical overview of MDM2/X-targeted therapies. Front Oncol 2016; 6: 7.
[http://dx.doi.org/10.3389/fonc.2016.00007] [PMID: 26858935]
[7]
Jeay S, Gaulis S, Ferretti S, et al. Correction: A distinct p53 target gene set predicts for response to the selective p53-HDM2 inhibitor NVP-CGM097. eLife 2016; 5e19317
[http://dx.doi.org/10.7554/eLife.19317] [PMID: 27852439]
[8]
Hong B, van den Heuvel AP, Prabhu VV, Zhang S, El-Deiry WS. Targeting tumor suppressor p53 for cancer therapy: Strategies, challenges and opportunities. Curr Drug Targets 2014; 15(1): 80-9.
[http://dx.doi.org/10.2174/1389450114666140106101412] [PMID: 24387333]
[9]
Walsh MF, Nathanson KL, Couch FJ, Offit K. Genomic biomarkers for breast cancer risk. Adv Exp Med Biol 2016; 882: 1-32.
[http://dx.doi.org/10.1007/978-3-319-22909-6_1] [PMID: 26987529]
[10]
Saini S. PSA and beyond: Alternative prostate cancer biomarkers. Cell Oncol (Dordr) 2016; 39(2): 97-106.
[http://dx.doi.org/10.1007/s13402-016-0268-6] [PMID: 26790878]
[11]
Iqbal N, Iqbal N. Human epidermal growth factor receptor 2 (HER2) in cancers: Overexpression and therapeutic implications. Mol Biol Int 2014; 2014852748.
[http://dx.doi.org/10.1155/2014/852748] [PMID: 25276427]
[12]
Ghodousi ES, Rahgozar S. MicroRNA-326 and microRNA-200c: Two novel biomarkers for diagnosis and prognosis of pediatric acute lymphoblastic leukemia. J Cell Biochem 2018; 119(7): 6024-32.
[http://dx.doi.org/10.1002/jcb.26800] [PMID: 29630744]
[13]
Aberuyi N, Rahgozar S, Khosravi Dehaghi Z, Moafi A, Masotti A, Paolini A. The translational expression of ABCA2 and ABCA3 is a strong prognostic biomarker for multidrug resistance in pediatric acute lymphoblastic leukemia. OncoTargets Ther 2017; 10: 3373-80.
[http://dx.doi.org/10.2147/OTT.S140488] [PMID: 28744141]
[14]
Rahgozar S, Moafi A, Abedi M, et al. mRNA expression profile of multidrug-resistant genes in acute lymphoblastic leukemia of children, a prognostic value for ABCA3 and ABCA2. Cancer Biol Ther 2014; 15(1): 35-41.
[http://dx.doi.org/10.4161/cbt.26603] [PMID: 24145140]
[15]
Dabaghi M, Rahgozar S, Moshtaghian J, Moafi A, Abedi M, Pourabutaleb E. Overexpression of SORCIN is a prognostic biomarker for multidrug-resistant pediatric acute lymphoblastic leukemia and correlates with upregulated MDR1/P-gp. Genet Test Mol Biomarkers 2016; 20(9): 516-21.
[http://dx.doi.org/10.1089/gtmb.2016.0031] [PMID: 27382961]
[16]
Chen M-B, Wu X-Y, Yu R, et al. P53 status as a predictive biomarker for patients receiving neoadjuvant radiation-based treatment: a meta-analysis in rectal cancer. PLoS One 2012; 7(9): e45388.
[http://dx.doi.org/10.1371/journal.pone.0045388] [PMID: 23049793]
[17]
Kandioler D, Schoppmann SF, Zwrtek R, et al. The biomarker TP53 divides patients with neoadjuvantly treated esophageal cancer into 2 subgroups with markedly different outcomes. A p53 Research Group study. J Thorac Cardiovasc Surg 2014; 148(5): 2280-6.
[http://dx.doi.org/10.1016/j.jtcvs.2014.06.079] [PMID: 25135238]
[18]
Oien DB, Chien J. TP53 mutations as a biomarker for high-grade serous ovarian cancer: Are we there yet? Transl Cancer Res 2016; S264-8.
[http://dx.doi.org/10.21037/tcr.2016.07.45]
[19]
Dahiya K, Dhankhar R. Updated overview of current biomarkers in head and neck carcinoma. World J Methodol 2016; 6(1): 77-86.
[http://dx.doi.org/10.5662/wjm.v6.i1.77] [PMID: 27018324]
[20]
Xiao M, Wang X, Chen W. The clinical translational potential of p53-related alterations as cancer biomarkers. Histol Histopathol 2015; 30(10): 1171-83.
[PMID: 26069201]
[21]
Duffy MJ, Synnott NC, McGowan PM, Crown J, O’Connor D, Gallagher WM. p53 as a target for the treatment of cancer. Cancer Treat Rev 2014; 40(10): 1153-60.
[http://dx.doi.org/10.1016/j.ctrv.2014.10.004] [PMID: 25455730]
[22]
Wade M, Li Y-C, Wahl GM. MDM2, MDMX and p53 in oncogenesis and cancer therapy. Nat Rev Cancer 2013; 13(2): 83-96.
[http://dx.doi.org/10.1038/nrc3430] [PMID: 23303139]
[23]
Shaikh ZNK. Tumour biology: p53 gene mechanisms. J Clin Cell Immunol 2015; 6(4)
[24]
Gupta A, Shah K, Oza MJ, Behl T. Reactivation of p53 gene by MDM2 inhibitors: A novel therapy for cancer treatment. Biomed Pharmacother 2019; 109: 484-92.
[http://dx.doi.org/10.1016/j.biopha.2018.10.155] [PMID: 30551517]
[25]
Hao Q, Cho WC. Battle against cancer: An everlasting saga of p53. Int J Mol Sci 2014; 15(12): 22109-27.
[http://dx.doi.org/10.3390/ijms151222109] [PMID: 25470027]
[26]
Kastenhuber ER, Lowe SW. Putting p53 in Context. Cell 2017; 170(6): 1062-78.
[http://dx.doi.org/10.1016/j.cell.2017.08.028] [PMID: 28886379]
[27]
Fischer M. Census and evaluation of p53 target genes. Oncogene 2017; 36(28): 3943-56.
[http://dx.doi.org/10.1038/onc.2016.502] [PMID: 28288132]
[28]
Shi D, Gu W. Dual roles of MDM2 in the regulation of p53: Ubiquitination dependent and ubiquitination independent mechanisms of MDM2 repression of p53 activity. Genes Cancer 2012; 3(3-4): 240-8.
[http://dx.doi.org/10.1177/1947601912455199] [PMID: 23150757]
[29]
Joerger ACFA, Fersht AR. The p53 pathway: Origins, inactivation in cancer, and emerging therapeutic approaches. Annu Rev Biochem 2016; 85(85): 375-404.
[http://dx.doi.org/10.1146/annurev-biochem-060815-014710] [PMID: 27145840]
[30]
Kamada R, Toguchi Y, Nomura T, Imagawa T, Sakaguchi K. Tetramer formation of tumor suppressor protein p53: Structure, function, and applications. Biopolymers 2016; 106(4): 598-612.
[http://dx.doi.org/10.1002/bip.22772] [PMID: 26572807]
[31]
Sullivan KD, Galbraith MD, Andrysik Z, Espinosa JM. Mechanisms of transcriptional regulation by p53. Cell Death Differ 2018; 25(1): 133-43.
[http://dx.doi.org/10.1038/cdd.2017.174] [PMID: 29125602]
[32]
Levine AJ, Ting DT, Greenbaum BD. P53 and the defenses against genome instability caused by transposons and repetitive elements. BioEssays 2016; 38(6): 508-13.
[http://dx.doi.org/10.1002/bies.201600031] [PMID: 27172878]
[33]
Wylie A, Jones AE, D’Brot A, et al. p53 genes function to restrain mobile elements. Genes Dev 2016; 30(1): 64-77.
[http://dx.doi.org/10.1101/gad.266098.115] [PMID: 26701264]
[34]
Mrakovcic M, Fröhlich LF. p53-mediated molecular control of autophagy in tumor cells. Biomolecules 2018; 8(2): 14.
[http://dx.doi.org/10.3390/biom8020014] [PMID: 29561758]
[35]
Cheng B, Lu J, Li T, et al. 1,3-Dichloro-2-Propanol inhibits autophagy via P53/AMPK/mTOR pathway in HepG2 cells. Food Chem Toxicol 2018; 122: 143-50.
[http://dx.doi.org/10.1016/j.fct.2018.10.030] [PMID: 30316840]
[36]
Alaee M, Padda A, Mehrabani V, Churchill L, Pasdar M. The physical interaction of p53 and plakoglobin is necessary for their synergistic inhibition of migration and invasion. Oncotarget 2016; 7(18): 26898-915.
[http://dx.doi.org/10.18632/oncotarget.8616] [PMID: 27058623]
[37]
Muñoz-Fontela C, Mandinova A, Aaronson SA, Lee SW. Emerging roles of p53 and other tumour-suppressor genes in immune regulation. Nat Rev Immunol 2016; 16(12): 741-50.
[http://dx.doi.org/10.1038/nri.2016.99] [PMID: 27667712]
[38]
Goldstein I, Ezra O, Rivlin N, et al. p53, a novel regulator of lipid metabolism pathways. J Hepatol 2012; 56(3): 656-62.
[http://dx.doi.org/10.1016/j.jhep.2011.08.022] [PMID: 22037227]
[39]
Assadian S, El-Assaad W, Wang XQD, et al. p53 inhibits angiogenesis by inducing the production of Arresten. Cancer Res 2012; 72(5): 1270-9.
[http://dx.doi.org/10.1158/0008-5472.CAN-11-2348] [PMID: 22253229]
[40]
Murphy ME. Ironing out how p53 regulates ferroptosis. Proc Natl Acad Sci USA 2016; 113(44): 12350-2.
[http://dx.doi.org/10.1073/pnas.1615159113] [PMID: 27791175]
[41]
Jiang L, Kon N, Li T, et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature 2015; 520(7545): 57-62.
[http://dx.doi.org/10.1038/nature14344] [PMID: 25799988]
[42]
Hermeking H. MicroRNAs in the p53 network: micromanagement of tumour suppression. Nat Rev Cancer 2012; 12(9): 613-26.
[http://dx.doi.org/10.1038/nrc3318] [PMID: 22898542]
[43]
Pappas K, Xu J, Zairis S, et al. p53 maintains baseline expression of multiple tumor suppressor genes. Mol Cancer Res 2017; 15(8): 1051-62.
[http://dx.doi.org/10.1158/1541-7786.MCR-17-0089] [PMID: 28483946]
[44]
Towers CG, Guarnieri AL, Micalizzi DS, et al. The Six1 oncoprotein downregulates p53 via concomitant regulation of RPL26 and microRNA-27a-3p. Nat Commun 2015; 6: 10077.
[http://dx.doi.org/10.1038/ncomms10077] [PMID: 26687066]
[45]
Liu J, Zhang C, Zhao Y, Feng Z. MicroRNA control of p53. J Cell Biochem 2017; 118(1): 7-14.
[http://dx.doi.org/10.1002/jcb.25609] [PMID: 27216701]
[46]
Teng Y, Yam GH-F, Li N, et al. MicroRNA regulation of MDM2-p53 loop in pterygium. Exp Eye Res 2018; 169: 149-56.
[http://dx.doi.org/10.1016/j.exer.2018.01.015] [PMID: 29360447]
[47]
Hu W, Chan CS, Wu R, et al. Negative regulation of tumor suppressor p53 by microRNA miR-504. Mol Cell 2010; 38(5): 689-99.
[http://dx.doi.org/10.1016/j.molcel.2010.05.027] [PMID: 20542001]
[48]
Herrero AB, Rojas EA, Misiewicz-Krzeminska I, Krzeminski P, Gutiérrez NC. Molecular mechanisms of p53 deregulation in cancer: An overview in multiple myeloma. Int J Mol Sci 2016; 17(12): 2003.
[http://dx.doi.org/10.3390/ijms17122003] [PMID: 27916892]
[49]
Kim H, Ronai ZA. Rewired Notch/p53 by Numb’ing Mdm2. J Cell Biol 2018; 217(2): 445-6.
[http://dx.doi.org/10.1083/jcb.201712007] [PMID: 29339436]
[50]
Perry ME. The regulation of the p53-mediated stress response by MDM2 and MDM4. Cold Spring Harb Perspect Biol 2010; 2(1): a000968.
[http://dx.doi.org/10.1101/cshperspect.a000968] [PMID: 20182601]
[51]
Lui K, An J, Montalbano J, et al. Negative regulation of p53 by Ras superfamily protein RBEL1A. J Cell Sci 2013; 126(Pt 11): 2436-45.
[http://dx.doi.org/10.1242/jcs.118117] [PMID: 23572512]
[52]
Collavin L, Lunardi A, Del Sal G. p53-family proteins and their regulators: hubs and spokes in tumor suppression. Cell Death Differ 2010; 17(6): 901-11.
[http://dx.doi.org/10.1038/cdd.2010.35] [PMID: 20379196]
[53]
Wang L, He G, Zhang P, Wang X, Jiang M, Yu L. Interplay between MDM2, MDMX, Pirh2 and COP1: The negative regulators of p53. Mol Biol Rep 2011; 38(1): 229-36.
[http://dx.doi.org/10.1007/s11033-010-0099-x] [PMID: 20333547]
[54]
Qi C-F, Kim Y-S, Xiang S, et al. Characterization of ARF-BP1/HUWE1 interactions with CTCF, MYC, ARF and p53 in MYC-driven B cell neoplasms. Int J Mol Sci 2012; 13(5): 6204-19.
[http://dx.doi.org/10.3390/ijms13056204] [PMID: 22754359]
[55]
Soto-Reyes E, Recillas-Targa F. Epigenetic regulation of the human p53 gene promoter by the CTCF transcription factor in transformed cell lines. Oncogene 2010; 29(15): 2217-27.
[http://dx.doi.org/10.1038/onc.2009.509] [PMID: 20101205]
[56]
Kumar M, Lu Z, Takwi AAL, et al. Negative regulation of the tumor suppressor p53 gene by microRNAs. Oncogene 2011; 30(7): 843-53.
[http://dx.doi.org/10.1038/onc.2010.457] [PMID: 20935678]
[57]
Swarbrick A, Woods SL, Shaw A, et al. miR-380-5p represses p53 to control cellular survival and is associated with poor outcome in MYCN-amplified neuroblastoma. Nat Med 2010; 16(10): 1134-40.
[http://dx.doi.org/10.1038/nm.2227] [PMID: 20871609]
[58]
Le MTN, Teh C, Shyh-Chang N, et al. MicroRNA-125b is a novel negative regulator of p53. Genes Dev 2009; 23(7): 862-76.
[http://dx.doi.org/10.1101/gad.1767609] [PMID: 19293287]
[59]
Cai B, Ma M, Chen B, et al. MiR-16-5p targets SESN1 to regulate the p53 signaling pathway, affecting myoblast proliferation and apoptosis, and is involved in myoblast differentiation. Cell Death Dis 2018; 9(3): 367.
[http://dx.doi.org/10.1038/s41419-018-0403-6] [PMID: 29511169]
[60]
Issler MVC, Mombach JCM. MicroRNA-16 feedback loop with p53 and Wip1 can regulate cell fate determination between apoptosis and senescence in DNA damage response. PLoS One 2017; 12(10): e0185794.
[http://dx.doi.org/10.1371/journal.pone.0185794] [PMID: 28968438]
[61]
Navarro F, Lieberman J. miR-34 and p53: New insights into a complex functional relationship. PLoS One 2015; 10(7): e0132767.
[http://dx.doi.org/10.1371/journal.pone.0132767] [PMID: 26177460]
[62]
Chen B, Wang J, Wang J, et al. A regulatory circuitry comprising TP53, miR-29 family, and SETDB1 in non-small cell lung cancer. Biosci Rep 2018; 38(5): BSR20180678.
[http://dx.doi.org/10.1042/BSR20180678] [PMID: 30054425]
[63]
Manfè V, Biskup E, Rosbjerg A, Kamstrup M, Skov AG, Lerche CM, et al. miR-122 regulates p53/Akt signalling and the chemotherapy-induced apoptosis in cutaneous T-cell lymphoma. PloS one 7(1): 2012;
[64]
Hock AK, Vousden KH. The role of ubiquitin modification in the regulation of p53. Biochim Biophys Acta 2014; 1843(1): 137-49.
[http://dx.doi.org/10.1016/j.bbamcr.2013.05.022] [PMID: 23742843]
[65]
Anil B, Riedinger C, Endicott JA, Noble MEM. The structure of an MDM2-Nutlin-3a complex solved by the use of a validated MDM2 surface-entropy reduction mutant. Acta Crystallogr D Biol Crystallogr 2013; 69(Pt 8): 1358-66.
[http://dx.doi.org/10.1107/S0907444913004459] [PMID: 23897459]
[66]
Fu T, Min H, Xu Y, Chen J, Li G. Molecular dynamic simulation insights into the normal state and restoration of p53 function. Int J Mol Sci 2012; 13(8): 9709-40.
[http://dx.doi.org/10.3390/ijms13089709] [PMID: 22949826]
[67]
Rew Y, Sun D, Yan X, et al. Discovery of AM-7209, a potent and selective 4-amidobenzoic acid inhibitor of the MDM2-p53 interaction. J Med Chem 2014; 57(24): 10499-511.
[http://dx.doi.org/10.1021/jm501550p] [PMID: 25384157]
[68]
Zhao Y, Aguilar A, Bernard D, Wang S. Small-molecule inhibitors of the MDM2-p53 protein-protein interaction (MDM2 Inhibitors) in clinical trials for cancer treatment. J Med Chem 2015; 58(3): 1038-52.
[http://dx.doi.org/10.1021/jm501092z] [PMID: 25396320]
[69]
Nag S, Qin J, Srivenugopal KS, Wang M, Zhang R. The MDM2-p53 pathway revisited. J Biomed Res 2013; 27(4): 254-71.
[PMID: 23885265]
[70]
Poyurovsky MV, Katz C, Laptenko O, et al. The C terminus of p53 binds the N-terminal domain of MDM2. Nat Struct Mol Biol 2010; 17(8): 982-9.
[http://dx.doi.org/10.1038/nsmb.1872] [PMID: 20639885]
[71]
Lee CW, Martinez-Yamout MA, Dyson HJ, Wright PE. Structure of the p53 transactivation domain in complex with the nuclear receptor coactivator binding domain of CREB binding protein. Biochemistry 2010; 49(46): 9964-71.
[http://dx.doi.org/10.1021/bi1012996] [PMID: 20961098]
[72]
Kulikov R, Winter M, Blattner C. Binding of p53 to the central domain of Mdm2 is regulated by phosphorylation. J Biol Chem 2006; 281(39): 28575-83.
[http://dx.doi.org/10.1074/jbc.M513311200] [PMID: 16870621]
[73]
Ma J, Martin JD, Zhang H, et al. A second p53 binding site in the central domain of Mdm2 is essential for p53 ubiquitination. Biochemistry 2006; 45(30): 9238-45.
[http://dx.doi.org/10.1021/bi060661u] [PMID: 16866370]
[74]
Zhang WW, Li L, Li D, et al. The first approved gene therapy product for cancer ad-p53 (gendicine): 12 years in the clinic. Hum Gene Ther 2018; 29(2): 160-79.
[http://dx.doi.org/10.1089/hum.2017.218] [PMID: 29338444]
[75]
Muller PA, Vousden KH. Mutant p53 in cancer: new functions and therapeutic opportunities. Cancer Cell 2014; 25(3): 304-17.
[http://dx.doi.org/10.1016/j.ccr.2014.01.021] [PMID: 24651012]
[78]
Grisham RN. Low-grade serous carcinoma of the ovary. Oncology (Williston Park) 2016; 30(7): 650-2.
[PMID: 27422112]
[79]
Comeaux EQ, Mullighan CG. TP53 mutations in hypodiploid acute lymphoblastic leukemia. Cold Spring Harb Perspect Med 2017; 7(3): a026286.
[http://dx.doi.org/10.1101/cshperspect.a026286] [PMID: 28003275]
[80]
Menezes J, Salgado RN, Acquadro F, et al. ASXL1, TP53 and IKZF3 mutations are present in the chronic phase and blast crisis of chronic myeloid leukemia. Blood Cancer J 2013; 3(11): e157.
[http://dx.doi.org/10.1038/bcj.2013.54] [PMID: 24212482]
[81]
Bohlman S, Manfredi JJ. p53-independent effects of Mdm2. Subcell Biochem 2014; 85: 235-46.
[http://dx.doi.org/10.1007/978-94-017-9211-0_13] [PMID: 25201198]
[82]
Wang S, Sun W, Zhao Y, et al. SAR405838: An optimized inhibitor of MDM2-p53 interaction that induces complete and durable tumor regression. Cancer Res 2014; 74(20): 5855-65.
[http://dx.doi.org/10.1158/0008-5472.CAN-14-0799] [PMID: 25145672]
[83]
Klein C, Vassilev LT. Targeting the p53-MDM2 interaction to treat cancer. Br J Cancer 2004; 91(8): 1415-9.
[http://dx.doi.org/10.1038/sj.bjc.6602164] [PMID: 15452548]
[84]
Zanjirband M, Edmondson RJ, Lunec J. Pre-clinical efficacy and synergistic potential of the MDM2-p53 antagonists, Nutlin-3 and RG7388, as single agents and in combined treatment with cisplatin in ovarian cancer. Oncotarget 2016; 7(26): 40115-34.
[http://dx.doi.org/10.18632/oncotarget.9499] [PMID: 27223080]
[85]
Fischer M, Uxa S, Stanko C, Magin TM, Engeland K. Human papilloma virus E7 oncoprotein abrogates the p53-p21-DREAM pathway. Sci Rep 2017; 7(1): 2603.
[http://dx.doi.org/10.1038/s41598-017-02831-9] [PMID: 28572607]
[86]
Reisman D, Takahashi P, Polson A, Boggs K. Transcriptional regulation of the p53 tumor suppressor gene in S-phase of the cell-cycle and the cellular response to DNA damage. Biochem Res Int 2012; 2012: 808934.
[http://dx.doi.org/10.1155/2012/808934] [PMID: 22830025]
[87]
Kracikova M, Akiri G, George A, Sachidanandam R, Aaronson SA. A threshold mechanism mediates p53 cell fate decision between growth arrest and apoptosis. Cell Death Differ 2013; 20(4): 576-88.
[http://dx.doi.org/10.1038/cdd.2012.155] [PMID: 23306555]
[88]
Kuribayashi K, Finnberg N, Jeffers JR, Zambetti GP, El-Deiry WS. The relative contribution of pro-apoptotic p53-target genes in the triggering of apoptosis following DNA damage in vitro and in vivo. Cell Cycle 2011; 10(14): 2380-9.
[http://dx.doi.org/10.4161/cc.10.14.16588] [PMID: 21709442]
[89]
Mir R, Tortosa A, Martinez-Soler F, et al. Mdm2 antagonists induce apoptosis and synergize with cisplatin overcoming chemoresistance in TP53 wild-type ovarian cancer cells. Int J Cancer 2013; 132(7): 1525-36.
[http://dx.doi.org/10.1002/ijc.27832] [PMID: 22961628]
[90]
Riley MF, Lozano G. The many faces of MDM2 binding partners. Genes Cancer 2012; 3(3-4): 226-39.
[http://dx.doi.org/10.1177/1947601912455322] [PMID: 23150756]
[91]
Taira N, Yamamoto H, Yamaguchi T, Miki Y, Yoshida K. ATM augments nuclear stabilization of DYRK2 by inhibiting MDM2 in the apoptotic response to DNA damage. J Biol Chem 2010; 285(7): 4909-19.
[http://dx.doi.org/10.1074/jbc.M109.042341] [PMID: 19965871]
[92]
Mo P, Wang H, Lu H, Boyd DD, Yan C. MDM2 mediates ubiquitination and degradation of activating transcription factor 3. J Biol Chem 2010; 285(35): 26908-15.
[http://dx.doi.org/10.1074/jbc.M110.132597] [PMID: 20592017]
[93]
Moumen A, Masterson P, O’Connor MJ, Jackson SP. hnRNP K: An HDM2 target and transcriptional coactivator of p53 in response to DNA damage. Cell 2005; 123(6): 1065-78.
[http://dx.doi.org/10.1016/j.cell.2005.09.032] [PMID: 16360036]
[94]
Galbán S, Duckett CS. XIAP as a ubiquitin ligase in cellular signaling. Cell Death Differ 2010; 17(1): 54-60.
[http://dx.doi.org/10.1038/cdd.2009.81] [PMID: 19590513]
[95]
Kawai H, Nie L, Wiederschain D, Yuan Z-M. Dual role of p300 in the regulation of p53 stability. J Biol Chem 2001; 276(49): 45928-32.
[http://dx.doi.org/10.1074/jbc.M107770200] [PMID: 11591713]
[96]
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.
[http://dx.doi.org/10.1146/annurev.pharmtox.48.113006.094723] [PMID: 18834305]
[97]
Lau LMS, Nugent JK, Zhao X, Irwin MS. HDM2 antagonist Nutlin-3 disrupts p73-HDM2 binding and enhances p73 function. Oncogene 2008; 27(7): 997-1003.
[http://dx.doi.org/10.1038/sj.onc.1210707] [PMID: 17700533]
[98]
Ambrosini G, Sambol EB, Carvajal D, Vassilev LT, Singer S, Schwartz GK. Mouse double minute antagonist Nutlin-3a enhances chemotherapy-induced apoptosis in cancer cells with mutant p53 by activating E2F1. Oncogene 2007; 26(24): 3473-81.
[http://dx.doi.org/10.1038/sj.onc.1210136] [PMID: 17146434]
[99]
LaRusch GA, Jackson MW, Dunbar JD, Warren RS, Donner DB, Mayo LD. Nutlin3 blocks vascular endothelial growth factor induction by preventing the interaction between hypoxia inducible factor 1α and Hdm2. Cancer Res 2007; 67(2): 450-4.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-2710] [PMID: 17234751]
[100]
Yang J-Y, Zong CS, Xia W, et al. ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation. Nat Cell Biol 2008; 10(2): 138-48.
[http://dx.doi.org/10.1038/ncb1676] [PMID: 18204439]
[101]
Gu L, Findley HW, Zhou M. MDM2 induces NF-kappaB/p65 expression transcriptionally through Sp1-binding sites: A novel, p53-independent role of MDM2 in doxorubicin resistance in acute lymphoblastic leukemia. Blood 2002; 99(9): 3367-75.
[http://dx.doi.org/10.1182/blood.V99.9.3367] [PMID: 11964305]
[102]
Gu L, Zhu N, Zhang H, Durden DL, Feng Y, Zhou M. Regulation of XIAP translation and induction by MDM2 following irradiation. Cancer Cell 2009; 15(5): 363-75.
[http://dx.doi.org/10.1016/j.ccr.2009.03.002] [PMID: 19411066]
[103]
Gu L, Zhang H, Liu T, et al. Discovery of dual inhibitors of MDM2 and XIAP for cancer treatment. Cancer Cell 2016; 30(4): 623-36.
[http://dx.doi.org/10.1016/j.ccell.2016.08.015] [PMID: 27666947]
[104]
Jin Y, Zeng SX, Dai M-S, Yang X-J, Lu H. MDM2 inhibits PCAF (p300/CREB-binding protein-associated factor)-mediated p53 acetylation. J Biol Chem 2002; 277(34): 30838-43.
[http://dx.doi.org/10.1074/jbc.M204078200] [PMID: 12068014]
[105]
Nieminen A-L, Qanungo S, Schneider EA, Jiang B-H, Agani FH. Mdm2 and HIF-1α interaction in tumor cells during hypoxia. J Cell Physiol 2005; 204(2): 364-9.
[http://dx.doi.org/10.1002/jcp.20406] [PMID: 15880652]
[106]
Conradt L, Henrich A, Wirth M, et al. Mdm2 inhibitors synergize with topoisomerase II inhibitors to induce p53-independent pancreatic cancer cell death. Int J Cancer 2013; 132(10): 2248-57.
[http://dx.doi.org/10.1002/ijc.27916] [PMID: 23115126]
[107]
Chène P. Inhibiting the p53-MDM2 interaction: An important target for cancer therapy. Nat Rev Cancer 2003; 3(2): 102-9.
[http://dx.doi.org/10.1038/nrc991] [PMID: 12563309]
[108]
Franklin M, Gentles L, Matheson E, et al. Characterization and drug sensitivity of a novel human ovarian clear cell carcinoma cell line genomically and phenotypically similar to the original tumor. Cancer Med 2018; 7(9): 4744-54.
[http://dx.doi.org/10.1002/cam4.1724] [PMID: 30109783]
[110]
ClinicalTrials.gov. National library of medicine http://www.clinicaltrials.gov
[111]
Shangary S, Qin D, McEachern D, et al. Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition. Proc Natl Acad Sci USA 2008; 105(10): 3933-8.
[http://dx.doi.org/10.1073/pnas.0708917105] [PMID: 18316739]
[112]
Ambrosini G1. Sambol EB, Carvajal D, Vassilev LT, Singer S, GK S. Mouse double minute antagonist Nutlin-3a enhances chemotherapy-induced apoptosis in cancer cells with mutant p53 by activating E2F1. Oncogene 2007; 24(26): 3473-81.
[113]
Andreeff M, Kelly KR, Yee K, et al. Results of the phase 1 trial of RG7112, a small-molecule MDM2 antagonist in leukemia. Clin Cancer Res 2016; 22(4): 868-76.
[http://dx.doi.org/10.1158/1078-0432.CCR-15-0481] [PMID: 26459177]
[114]
Ribeiro CJA, Rodrigues CMP, Moreira R, Santos MMM. Chemical variations on the p53 reactivation theme. Pharmaceuticals (Basel) 2016; 9(2): 25.
[http://dx.doi.org/10.3390/ph9020025] [PMID: 27187415]
[115]
Tovar C, Graves B, Packman K, et al. MDM2 small-molecule antagonist RG7112 activates p53 signaling and regresses human tumors in preclinical cancer models. Cancer Res 2013; 73(8): 2587-97.
[http://dx.doi.org/10.1158/0008-5472.CAN-12-2807] [PMID: 23400593]
[116]
Vu B, Wovkulich P, Pizzolato G, et al. Discovery of RG7112: A small-molecule MDM2 inhibitor in clinical development. ACS Med Chem Lett 2013; 4(5): 466-9.
[http://dx.doi.org/10.1021/ml4000657] [PMID: 24900694]
[117]
Tovar C, Higgins B, Kolinsky K, et al. MDM2 antagonists boost antitumor effect of androgen withdrawal: Implications for therapy of prostate cancer. Mol Cancer 2011; 10: 49.
[http://dx.doi.org/10.1186/1476-4598-10-49] [PMID: 21539745]
[118]
Carol H, Reynolds CP, Kang MH, et al. Initial testing of the MDM2 inhibitor RG7112 by the Pediatric Preclinical Testing Program. Pediatr Blood Cancer 2013; 60(4): 633-41.
[http://dx.doi.org/10.1002/pbc.24235] [PMID: 22753001]
[119]
Ray-Coquard I, Blay J-Y, Italiano A, 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(11): 1133-40.
[http://dx.doi.org/10.1016/S1470-2045(12)70474-6] [PMID: 23084521]
[120]
Tisato V, Voltan R, Gonelli A, Secchiero P, Zauli G. MDM2/X inhibitors under clinical evaluation: Perspectives for the management of hematological malignancies and pediatric cancer. J Hematol Oncol 2017; 10(1): 133.
[http://dx.doi.org/10.1186/s13045-017-0500-5] [PMID: 28673313]
[121]
Ludwig RL, Bates S, Vousden KH. Differential activation of target cellular promoters by p53 mutants with impaired apoptotic function. Mol Cell Biol 1996; 16(9): 4952-60.
[http://dx.doi.org/10.1128/MCB.16.9.4952] [PMID: 8756654]
[122]
Yeudall WA, Vaughan CA, Miyazaki H, et al. Gain-of-function mutant p53 upregulates CXC chemokines and enhances cell migration. Carcinogenesis 2012; 33(2): 442-51.
[http://dx.doi.org/10.1093/carcin/bgr270] [PMID: 22114072]
[123]
Ding Q, Zhang Z, Liu J-J, et al. Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development. J Med Chem 2013; 56(14): 5979-83.
[http://dx.doi.org/10.1021/jm400487c] [PMID: 23808545]
[124]
Herting F, Herter S, Friess T, 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(5): 461-70.
[http://dx.doi.org/10.1111/ejh.12756] [PMID: 26993060]
[125]
Chen L, Rousseau RF, Middleton SA, et al. Pre-clinical evaluation of the MDM2-p53 antagonist RG7388 alone and in combination with chemotherapy in neuroblastoma. Oncotarget 2015; 6(12): 10207-21.
[http://dx.doi.org/10.18632/oncotarget.3504] [PMID: 25844600]
[126]
Lakoma A, Barbieri E, Agarwal S, et al. The MDM2 small-molecule inhibitor RG7388 leads to potent tumor inhibition in p53 wild-type neuroblastoma. Cell Death Discov 2015; 1: 15026.
[http://dx.doi.org/10.1038/cddiscovery.2015.26] [PMID: 26998348]
[127]
Van Goethem A, Yigit N, Moreno-Smith M, et al. Dual targeting of MDM2 and BCL2 as a therapeutic strategy in neuroblastoma. Oncotarget 2017; 8(34): 57047-57.
[http://dx.doi.org/10.18632/oncotarget.18982] [PMID: 28915653]
[128]
Zanjirband M, Curtin N, Edmondson RJ, Lunec J. Combination treatment with rucaparib (Rubraca) and MDM2 inhibitors, Nutlin-3 and RG7388, has synergistic and dose reduction potential in ovarian cancer. Oncotarget 2017; 8(41): 69779-96.
[http://dx.doi.org/10.18632/oncotarget.19266] [PMID: 29050241]
[129]
Seipel K, Marques MAT, Sidler C, Mueller BU, Pabst T. Pabst BUMaT. The cellular p53 inhibitor MDM2 and the growth factor receptor FLT3 as biomarkers for treatment responses to the MDM2-inhibitor Idasanutlin and the MEK1 inhibitor cobimetinib in acute myeloid leukemia. Cancers (Basel) 2018; 10(6): 170.
[http://dx.doi.org/10.3390/cancers10060170] [PMID: 29857559]
[130]
Higgins B, Glenn K, Walz A, et al. Preclinical optimization of MDM2 antagonist scheduling for cancer treatment by using a model-based approach. Clin Cancer Res 2014; 20(14): 3742-52.
[http://dx.doi.org/10.1158/1078-0432.CCR-14-0460] [PMID: 24812409]
[131]
Manoharan V, Lunec J, Esfandiari A, Mahdi A, Wu C-E, Zan-jirband M, et al. Abstract P3-07-21: Cytotoxic potential of the RG7388 MDM2-p53 binding antagonist and the GSK2830371 WIP1 inhibitor on MX-1 and MCF-7 human breast cancer cells. Cancer Res 2017; 77(4)((Supplement).).
[132]
Hai J, Sakashita S, Allo G, et al. Inhibiting MDM2-p53 interaction suppresses tumor growth in patient-derived non–small cell lung cancer xenograft models. J Thorac Oncol 2015; 10(8): 1172-80.
[http://dx.doi.org/10.1097/JTO.0000000000000584] [PMID: 26200271]
[133]
Umamaheswari N, Thiagarajan V, Vijayaraghavan R, Shila SRA. Comparative effects of HDAC inhibitor SAHA and MDM2 inhibitor RG7388 in LNCaP prostate cancer cells. Biomed J Sci Tech Res 2018; 8(4): 677.
[134]
Siu LL, Italiano A, Miller WH, Blay J-Y, Gietema JA, Bang Y-J, 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(15_suppl).
[135]
Reis B, Jukofsky L, Chen G, et al. Acute myeloid leukemia patients’ clinical response to idasanutlin (RG7388) is associated with pre-treatment MDM2 protein expression in leukemic blasts. Haematologica 2016; 101(5): e185-8.
[http://dx.doi.org/10.3324/haematol.2015.139717] [PMID: 26869629]
[136]
Koblish HK, Zhao S, Franks CF, et al. Benzodiazepinedione inhibitors of the Hdm2: p53 complex suppress human tumor cell proliferation in vitro and sensitize tumors to doxorubicin in vivo. Mol Cancer Ther 2006; 5(1): 160-9.
[http://dx.doi.org/10.1158/1535-7163.MCT-05-0199] [PMID: 16432175]
[137]
Grasberger BL, Lu T, Schubert C, et al. Discovery and cocrystal structure of benzodiazepinedione HDM2 antagonists that activate p53 in cells. J Med Chem 2005; 48(4): 909-12.
[http://dx.doi.org/10.1021/jm049137g] [PMID: 15715460]
[138]
Canner JA, Sobo M, Ball S, et al. MI-63: A novel small-molecule inhibitor targets MDM2 and induces apoptosis in embryonal and alveolar rhabdomyosarcoma cells with wild-type p53. Br J Cancer 2009; 101(5): 774-81.
[http://dx.doi.org/10.1038/sj.bjc.6605199] [PMID: 19707204]
[139]
Sosin AM, Burger AM, Siddiqi A, Abrams J, Mohammad RM, Al-Katib AM. HDM2 antagonist MI-219 (spiro-oxindole), but not Nutlin-3 (cis-imidazoline), regulates p53 through enhanced HDM2 autoubiquitination and degradation in human malignant B-cell lymphomas. J Hematol Oncol 2012; 5: 57.
[http://dx.doi.org/10.1186/1756-8722-5-57] [PMID: 22989009]
[140]
Bill KLJ, Garnett J, Meaux I, et al. SAR405838: A novel and potent inhibitor of the MDM2: p53 axis for the treatment of dedifferentiated liposarcoma. Clin Cancer Res 2016; 22(5): 1150-60.
[http://dx.doi.org/10.1158/1078-0432.CCR-15-1522] [PMID: 26475335]
[141]
de Jonge M, de Weger VA, Dickson MA, et al. A phase I study of SAR405838, a novel human double minute 2 (HDM2) antagonist, in patients with solid tumours. Eur J Cancer 2017; 76: 144-51.
[http://dx.doi.org/10.1016/j.ejca.2017.02.005] [PMID: 28324749]
[142]
de Weger VA, de Jonge M, Langenberg MHG, et al. A phase I study of the HDM2 antagonist SAR405838 combined with the MEK inhibitor pimasertib in patients with advanced solid tumours. Br J Cancer 2019; 120(3): 286-93.
[http://dx.doi.org/10.1038/s41416-018-0355-8] [PMID: 30585255]
[143]
Canon J, Osgood T, Olson SH, 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(3): 649-58.
[http://dx.doi.org/10.1158/1535-7163.MCT-14-0710] [PMID: 25567130]
[144]
Werner LR, Huang S, Francis DM, et al. Small molecule inhibition of MDM2–p53 interaction augments radiation response in human tumors. Mol Cancer Ther 2015; 14(9): 1994-2003.
[http://dx.doi.org/10.1158/1535-7163.MCT-14-1056-T] [PMID: 26162687]
[145]
Ravandi F, Gojo I, Patnaik MM, et al. A phase I trial of the human double minute 2 inhibitor (MK-8242) in patients with refractory/recurrent acute myelogenous leukemia (AML). Leuk Res 2016; 48: 92-100.
[http://dx.doi.org/10.1016/j.leukres.2016.07.004] [PMID: 27544076]
[146]
Wagner AJ, Banerji U, Mahipal A, et al. Phase I trial of the human double minute 2 inhibitor MK-8242 in patients with advanced solid tumors. J Clin Oncol 2017; 35(12): 1304-11.
[http://dx.doi.org/10.1200/JCO.2016.70.7117] [PMID: 28240971]
[147]
Wagner AJ, Banerji U, Mahipal A, et al. Phase I trial of the human double minute 2 inhibitor MK-8242 in patients with advanced solid tumors. J Clin Oncol 2017; 35(12): 1304-11.
[http://dx.doi.org/10.1200/JCO.2016.70.7117] [PMID: 28240971]
[148]
Holzer P, Masuya K, Furet P, 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(16): 6348-58.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00810] [PMID: 26181851]
[149]
Weisberg E, Halilovic E, Cooke VG, et al. Inhibition of wild-type p53-expressing AML by novel small molecule HDM2 inhibitor, CGM097. Mol Cancer Ther 2015; 14(10): 2249-59.
[http://dx.doi.org/10.1158/1535-7163.MCT-15-0429] [PMID: 26206331]
[150]
Reuther C, Heinzle V, Nölting S, et al. The HDM2 (MDM2) inhibitor NVP-CGM097 inhibits tumor cell proliferation and shows additive effects with 5-Fluorouracil on the p53-p21-Rb-E2F1 cascade in the p53 wild type neuroendocrine tumor cell line GOT1. Neuroendocrinology 2018; 106(1): 1-19.
[http://dx.doi.org/10.1159/000453369] [PMID: 27871087]
[151]
Arnhold V, Schmelz K, Proba J, et al. Reactivating TP53 signaling by the novel MDM2 inhibitor DS-3032b as a therapeutic option for high-risk neuroblastoma. Oncotarget 2017; 9(2): 2304-19.
[PMID: 29416773]
[152]
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).
[153]
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).
[154]
DiNardo CD, Rosenthal J, Andreeff M, et al. Phase 1 dose escalation study of MDM2 inhibitor DS-3032b in patients with hematological malignancies - preliminary results. Blood 2016; 128(22): 593.
[155]
Furet P, Masuya K, Kallen J, et al. Discovery of a novel class of highly potent inhibitors of the p53-MDM2 interaction by structure-based design starting from a conformational argument. Bioorg Med Chem Lett 2016; 26(19): 4837-41.
[http://dx.doi.org/10.1016/j.bmcl.2016.08.010] [PMID: 27542305]
[156]
Ferretti S, Rebmann R, Berger M, et al. Abstract 1224: 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(Suppl. 14): 1224.
[157]
Hyman D, Chatterjee M, Langenberg MHG, Lin CC, Suárez C, Tai D, et al. Dose- and regimen-finding phase I study of NVP-HDM201 in patients (pts) with TP53 wild-type (wt) advanced tumors. Eur J Cancer 2016; 69: S128-9.
[http://dx.doi.org/10.1016/S0959-8049(16)32982-3]
[158]
Espinosa JM, Sullivan KD. A signature for success. eLife 2015 4e08773
[http://dx.doi.org/10.7554/eLife.08773] [PMID: 26079875]
[159]
Sonkin D. Expression signature based on TP53 target genes doesn’t predict response to TP53-MDM2 inhibitor in wild type TP53 tumors. eLife 2015; 4e10279.
[http://dx.doi.org/10.7554/eLife.10279] [PMID: 26491944]
[160]
Lane DP, Cheok CF, Lain S. p53-based cancer therapy. Cold Spring Harb Perspect Biol 2010; 2(9): a001222.
[http://dx.doi.org/10.1101/cshperspect.a001222] [PMID: 20463003]
[161]
Mendrysa SM, McElwee MK, Michalowski J, O’Leary KA, Young KM, Perry ME. mdm2 Is critical for inhibition of p53 during lymphopoiesis and the response to ionizing irradiation. Mol Cell Biol 2003; 23(2): 462-72.
[http://dx.doi.org/10.1128/MCB.23.2.462-473.2003] [PMID: 12509446]
[162]
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(2): 137-45.e5.
[http://dx.doi.org/10.1016/j.exphem.2013.11.012] [PMID: 24309210]
[163]
Mahfoudhi E, Lordier L, Marty C, et al. P53 activation inhibits all types of hematopoietic progenitors and all stages of megakaryopoiesis. Oncotarget 2016; 7(22): 31980-92.
[http://dx.doi.org/10.18632/oncotarget.7881] [PMID: 26959882]
[164]
Worrall C, Suleymanova N, Crudden C, et al. Unbalancing p53/Mdm2/IGF-1R axis by Mdm2 activation restrains the IGF-1-dependent invasive phenotype of skin melanoma. Oncogene 2017; 36(23): 3274-86.
[http://dx.doi.org/10.1038/onc.2016.472] [PMID: 28092675]
[165]
Aziz MH, Shen H, Maki CG. Acquisition of p53 mutations in response to the non-genotoxic p53 activator Nutlin-3. Oncogene 2011; 30(46): 4678-86.
[http://dx.doi.org/10.1038/onc.2011.185] [PMID: 21643018]
[166]
Michaelis M, Rothweiler F, Barth S, et al. Adaptation of cancer cells from different entities to the MDM2 inhibitor nutlin-3 results in the emergence of p53-mutated multi-drug-resistant cancer cells. Cell Death Dis 2011; 2(12): e243.
[http://dx.doi.org/10.1038/cddis.2011.129] [PMID: 22170099]
[167]
Yang W, Soares J, Greninger P, et al. Genomics of Drug Sensitivity in Cancer (GDSC): A resource for therapeutic biomarker discovery in cancer cells. Nucleic Acids Res 2013; 41(Database issue): D955-61.
[PMID: 23180760]
[168]
Drummond CJ, Esfandiari A, Liu J, et al. TP53 mutant MDM2-amplified cell lines selected for resistance to MDM2-p53 binding antagonists retain sensitivity to ionizing radiation. Oncotarget 2016; 7(29): 46203-18.
[http://dx.doi.org/10.18632/oncotarget.10073] [PMID: 27323823]
[169]
Wu C-E, Koay TS, Ho Y-H, Lovat P, Lunec J. TP53 mutant cell lines selected for resistance to MDM2 inhibitors retain growth inhibition by MAPK pathway inhibitors but a reduced apoptotic response. Cancer Cell Int 2019; 19(1): 53.
[http://dx.doi.org/10.1186/s12935-019-0768-3] [PMID: 30899200]
[170]
Du W, Searle JS. The rb pathway and cancer therapeutics. Curr Drug Targets 2009; 10(7): 581-9.
[http://dx.doi.org/10.2174/138945009788680392] [PMID: 19601762]
[171]
Esfandiari A, Hawthorne TA, Nakjang S, Lunec J. Chemical inhibition of wild-type p53-induced phosphatase 1 (WIP1/PPM1D) by GSK2830371 potentiates the sensitivity to MDM2 inhibitors in a p53-dependent manner. Mol Cancer Ther 2016; 15(3): 379-91.
[http://dx.doi.org/10.1158/1535-7163.MCT-15-0651] [PMID: 26832796]
[172]
Tan BX, Khoo KH, Lim TM, Lane DP. High Mdm4 levels suppress p53 activity and enhance its half-life in acute myeloid leukaemia. Oncotarget 2014; 5(4): 933-43.
[http://dx.doi.org/10.18632/oncotarget.1559] [PMID: 24659749]
[173]
Chapeau EA, Gembarska A, Durand EY, et al. Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf-/- mouse model. Proc Natl Acad Sci USA 2017; 114(12): 3151-6.
[http://dx.doi.org/10.1073/pnas.1620262114] [PMID: 28265066]
[174]
Berberich A, Kessler T, Thomé CM, et al. Targeting resistance against the MDM2 inhibitor RG7388 in glioblastoma cells by the MEK inhibitor trametinib. Clin Cancer Res 2019; 25(1): 253-65.
[http://dx.doi.org/10.1158/1078-0432.CCR-18-1580] [PMID: 30274984]
[175]
Teoh PJ, Chng WJ. p53 abnormalities and potential therapeutic targeting in multiple myeloma. BioMed Res Int 2014; 2014717919.
[http://dx.doi.org/10.1155/2014/717919] [PMID: 25028664]
[176]
Murray MY, Rushworth SA, Zaitseva L, Bowles KM, Macewan DJ. Attenuation of dexamethasone-induced cell death in multiple myeloma is mediated by miR-125b expression. Cell Cycle 2013; 12(13): 2144-53.
[http://dx.doi.org/10.4161/cc.25251] [PMID: 23759586]
[177]
Chou T-C. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res 2010; 70(2): 440-6.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-1947] [PMID: 20068163]
[178]
Prabakaran PJ, Javaid AM, Swick AD, et al. Radiosensitization of adenoid cystic carcinoma with MDM2 inhibition. Clin Cancer Res 2017; 23(20): 6044-53.
[http://dx.doi.org/10.1158/1078-0432.CCR-17-0969] [PMID: 28659312]
[179]
Deben C, Wouters A, Op de Beeck K, et al. The MDM2-inhibitor Nutlin-3 synergizes with cisplatin to induce p53 dependent tumor cell apoptosis in non-small cell lung cancer. Oncotarget 2015; 6(26): 22666-79.
[http://dx.doi.org/10.18632/oncotarget.4433] [PMID: 26125230]
[180]
Coll-Mulet L, Iglesias-Serret D, Santidrián AF, et al. MDM2 antagonists activate p53 and synergize with genotoxic drugs in B-cell chronic lymphocytic leukemia cells. Blood 2006; 107(10): 4109-14.
[http://dx.doi.org/10.1182/blood-2005-08-3273] [PMID: 16439685]
[181]
Pishas KI, Al-Ejeh F, Zinonos I, et al. Nutlin-3a is a potential therapeutic for ewing sarcoma. Clin Cancer Res 2011; 17(3): 494-504.
[http://dx.doi.org/10.1158/1078-0432.CCR-10-1587] [PMID: 21098696]
[182]
Laroche-Clary A, Chaire V, Algeo M-P, Derieppe M-A, Loarer FL, Italiano A. Combined targeting of MDM2 and CDK4 is synergistic in dedifferentiated liposarcomas. J Hematol Oncol 2017; 10(1): 123.
[http://dx.doi.org/10.1186/s13045-017-0482-3] [PMID: 28629371]
[183]
Wang HQ, Halilovic E, Li X, et al. Combined ALK and MDM2 inhibition increases antitumor activity and overcomes resistance in human ALK mutant neuroblastoma cell lines and xenograft models. eLife 2017; 6e17137
[184]
Trino S, De Luca L, Laurenzana I, et al. P53-MDM2 pathway: Evidences for a new targeted therapeutic approach in B-acute lymphoblastic leukemia. Front Pharmacol 2016; 7: 491.
[http://dx.doi.org/10.3389/fphar.2016.00491] [PMID: 28018226]
[185]
Stengel A, Schnittger S, Weissmann S, et al. TP53 mutations occur in 15.7% of ALL and are associated with MYC-rearrangement, low hypodiploidy, and a poor prognosis. Blood 2014; 124(2): 251-8.
[http://dx.doi.org/10.1182/blood-2014-02-558833] [PMID: 24829203]
[186]
Rossi D, Gaidano G. The clinical implications of gene mutations in chronic lymphocytic leukaemia. Br J Cancer 2016; 114(8): 849-54.
[http://dx.doi.org/10.1038/bjc.2016.78] [PMID: 27031852]
[187]
Richmond J, Carol H, Evans K, et al. Effective targeting of the P53-MDM2 axis in preclinical models of infant MLL-rearranged acute lymphoblastic leukemia. Clin Cancer Res 2015; 21(6): 1395-405.
[http://dx.doi.org/10.1158/1078-0432.CCR-14-2300] [PMID: 25573381]
[188]
Soverini S, De Benedittis C, Papayannidis C, et al. Drug resistance and BCR-ABL kinase domain mutations in Philadelphia chromosome-positive acute lymphoblastic leukemia from the imatinib to the second-generation tyrosine kinase inhibitor era: The main changes are in the type of mutations, but not in the frequency of mutation involvement. Cancer 2014; 120(7): 1002-9.
[http://dx.doi.org/10.1002/cncr.28522] [PMID: 24382642]
[189]
Köbel M, Kalloger SE, Boyd N, et al. Ovarian carcinoma subtypes are different diseases: Implications for biomarker studies. PLoS Med 2008; 5(12): e232.
[http://dx.doi.org/10.1371/journal.pmed.0050232] [PMID: 19053170]
[190]
Makii C, Oda K, Ikeda Y, et al. MDM2 is a potential therapeutic target and prognostic factor for ovarian clear cell carcinomas with wild type TP53. Oncotarget 2016; 7(46): 75328-38.
[http://dx.doi.org/10.18632/oncotarget.12175] [PMID: 27659536]


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VOLUME: 20
ISSUE: 11
Year: 2019
Page: [1091 - 1111]
Pages: 21
DOI: 10.2174/1389450120666190402120701
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