Prima-1 and APR-246 in Cancer Therapy

Česká verzia

Authors: Zatloukalová Pavlína; Galoczová Michaela; Vojtěšek Bořivoj
Authors place of work: Regionální centrum aplikované molekulární onkologie, Masarykův onkologický ústav, Brno
Published in the journal: Klin Onkol 2018; 31(Supplementum 2): 71-76
Category: Review
doi: https://doi.org/10.14735/amko20182S71

Summary

Background:

p53 is the most mutated protein in cancer and the reactivation of its inactive mutated form represents one possibility for antitumor therapy. Reactivation leads to the initiation of apoptosis followed by the suppression of the malignant phenotype. Prima-1 and its methylated form Prima-1^Met (also called APR-246) are compounds capable of reactivating mutated p53. Both are low-molecular substances that have been tested in a number of tumor cell lines and tumors bearing mutated p53.

Aim:

This article summarizes what is currently known about both compounds, describes the possibilities of their use in anti-tumor therapy, and outlines the results of currently undergoing clinical trials of APR-246.

Conclusion:

The results show that the mechanism of action of both compounds is still not clear. The mechanism is only known clearly in the case of Prima-1, and APR-246 is only known to induce apoptosis. The specificity of both substances for mutated p53 differs considerably and depends mainly on the cell model employed and the type of mutation. In addition to p53 reactivation itself, these compounds likely influence other mechanisms that also affect cytotoxic activity.

Key words:

Prima-1^Met – APR-246 – Prima-1 – reactivation of p53 – apoptosis

NPU I – LO1413. This work was supported by the project MEYS – NPS I – LO1413.

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.

Accepted: 16. 07. 2018

Zdroje

1. Kandoth C, McLellan MD, Vandin F et al. Mutational landscape and significance across 12 major cancer types. Nature 2013; 502 (7471): 333–339. doi: 10.1038/nature12634.

2. Duffy MJ, Synnott NC, Crown J. Mutant p53 as a target for cancer treatment. Eur J Cancer 2017; 83: 258–265. doi: 10.1016/j.ejca.2017.06.023.

3. Bieging KT, Mello SS, Attardi LD. Unravelling mechanisms of p53-mediated tumour suppression. Nat Rev Cancer 2014; 14 (5): 359–370. doi: 10.1038/nrc3711.

4. Selivanova G, Wiman KG. Reactivation of mutant p53: molecular mechanisms and therapeutic potential. Oncogene 2007; 26 (15): 2243–2254. doi: 10.1038/sj.onc.1210295.

5. Lane DP. Cancer. p53, guardian of the genome. Nature 1992; 358 (6381): 15–16. doi: 10.1038/358015a0.

6. Brosh R, Rotter V. When mutants gain new powers: news from the mutant p53 field. Nat Rev Cancer 2009; 9 (10): 701–713. doi: 10.1038/nrc2693.

7. Bykov VJ, Issaeva N, Zache N et al. Reactivation of mutant p53 and induction of apoptosis in human tumor cells by maleimide analogs. J Biol Chem 2005; 280 (34): 30384–30391. doi: 10.1074/jbc.M501664200.

8. Luu Y, Bush J, Cheung KJ Jr et al. The p53 stabilizing compound CP-31398 induces apoptosis by activating the intrinsic Bax/mitochondrial/caspase-9 pathway. Exp Cell Res 2002; 276 (2): 214–222. doi: 10.1006/excr.2002.5526.

9. Boeckler FM, Joerger AC, Jaggi G et al. Targeted rescue of a destabilized mutant of p53 by an in silico screened drug. Proc Natl Acad Sci U S A 2008; 105 (30): 10360–10365. doi: 10.1073/pnas.0805326105.

10. Bykov VJ, Issaeva N, Selivanova G et al. Mutant p53-dependent growth suppression distinguishes PRIMA-1 from known anticancer drugs: a statistical analysis of information in the National Cancer Institute database. Carcinogenesis 2002; 23 (12): 2011–2018.

11. Bykov VJ, Zache N, Stridh H et al. PRIMA-1 (MET) synergizes with cisplatin to induce tumor cell apoptosis. Oncogene 2005; 24 (21): 3484–3491. doi: 10.1038/sj.onc.1208419.

12. Bykov VJ, Issaeva N, Shilov A et al. Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound. Nat Med 2002; 8 (3): 282–288. doi: 10.1038/nm0302-282.

13. Lambert JM, Gorzov P, Veprintsev DB et al. PRIMA-1 reactivates mutant p53 by covalent binding to the core domain. Cancer Cell 2009; 15 (5): 376–388. doi: 10.1016/j.ccr.2009.03.003.

14. Wassman CD, Baronio R, Demir Ö et al. Computational identification of a transiently open L1/S3 pocket for reactivation of mutant p53. Nat Commun 2013; 4: 1407. doi: 10.1038/ncomms2361.

15. Kaar JL, Basse N, Joerger AC et al. Stabilization of mutant p53 via alkylation of cysteines and effects on DNA binding. Protein Sci 2010; 19 (12): 2267–2278. doi: 10.1002/pro.507.

16. Zhang Q, Bykov VJN, Wiman KG et al. APR-246 reactivates mutant p53 by targeting cysteines 124 and 277. Cell Death Dis 2018; 9 (5): 439. doi: 10.1038/s41419-018-0463-7.

17. Rehman A, Chahal MS, Tang X et al. Proteomic identification of heat shock protein 90 as a candidate target for p53 mutation reactivation by PRIMA-1 in breast cancer cells. Breast Cancer Res 2005; 7 (5): R765–R774. doi: 10.1186/bcr1290.

18. Aryee DN, Niedan S, Ban J et al. Variability in functional p53 reactivation by PRIMA-1 (Met) /APR-246 in Ewing sarcoma. Br J Cancer 2013; 109 (10): 2696–2704. doi: 10.1038/bjc.2013.635.

19. Lambert JM, Moshfegh A, Hainaut P et al. Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene 2010; 29 (9): 1329–1338. doi: 10.1038/onc.2009.425.

20. Zandi R, Selivanova G, Christensen CL et al. PRIMA-1Met/APR-246 induces apoptosis and tumor growth delay in small cell lung cancer expressing mutant p53. Clin Cancer Res 2011; 17 (9): 2830–2841. doi: 10.1158/1078-0432.CCR-10-3168.

21. Bykov VJN, Eriksson SE, Bianchi J et al. Targeting mutant p53 for efficient cancer therapy. Nat Rev Cancer 2018; 18 (2): 89–102. doi: 10.1038/nrc.2017.109.

22. Liu DS, Read M, Cullinane C et al. APR-246 potently inhibits tumour growth and overcomes chemoresistance in preclinical models of oesophageal adenocarcinoma. Gut 2015; 64 (10): 1506–1516. doi: 10.1136/gutjnl-2015-309770.

23. Peng X, Zhang MQ, Conserva F et al. APR-246/PRIMA-1MET inhibits thioredoxin reductase 1 and converts the enzyme to a dedicated NADPH oxidase. Cell Death Dis 2013; 4: e881. doi: 10.1038/cddis.2013.417.

24. Teoh PJ, Bi C, Sintosebastian C et al. PRIMA-1 targets the vulnerability of multiple myeloma of deregulated protein homeostasis through the perturbation of ER stress via p73 demethylation. Oncotarget 2016; 7 (38): 61806–61819. doi: 10.18632/oncotarget.11241.

25. Shen J, Vakifahmetoglu H, Stridh H et al. PRIMA-1MET induces mitochondrial apoptosis through activation of caspase-2. Oncogene 2008; 27 (51): 6571–6580. doi: 10.1038/onc.2008.249.

26. Bao W, Chen M, Zhao X et al. PRIMA-1Met/APR-246 induces wild-type p53-dependent suppression of malignant melanoma tumor growth in 3D culture and in vivo. Cell Cycle 2011; 10 (2): 301–307. doi: 10.4161/cc.10.2.14538.

27. Magrini R, Russo D, Ottaggio L et al. PRIMA-1 synergizes with adriamycin to induce cell death in non-small cell lung cancer cells. J Cell Biochem 2008; 104 (6): 2363–2373. doi: 10.1002/jcb.21794.

28. Supiot S, Zhao H, Wiman K et al. PRIMA-1 (met) radiosensitizes prostate cancer cells independent of their MTp53-status. Radiother Oncol 2008; 86 (3): 407–411. doi: 10.1016/j.radonc.2008.01.001.

29. Grellety T, Laroche-Clary A, Chaire V et al. PRIMA-1 (MET) induces death in soft-tissue sarcomas cell independent of p53. BMC Cancer 2015; 15: 684. doi: 10.1186/s12885-015-1667-1.

30. Li Y, Mao Y, Brandt-Rauf PW et al. Selective induction of apoptosis in mutant p53 premalignant and malignant cancer cells by PRIMA-1 through the c-Jun-NH2-kinase pathway. Mol Cancer Ther 2005; 4 (6): 901–909. doi: 10.1158/1535-7163.MCT-04-0206.

31. Wang T, Lee K, Rehman A et al. PRIMA-1 induces apoptosis by inhibiting JNK signaling but promoting the activation of Bax. Biochem Biophys Res Commun 2007; 352 (1): 203–212. doi: 10.1016/j.bbrc.2006.11.006.

32. Yin ZX, Hang W, Liu G et al. PARP-1 inhibitors sensitize HNSCC cells to APR-246 by inactivation of thioredoxin reductase 1 (TrxR1) and promotion of ROS accumulation. Oncotarget 2018; 9 (2): 1885–1897. doi: 10.18632/oncotarget.21277.

33. Tessoulin B, Descamps G, Moreau P et al. PRIMA-1Met induces myeloma cell death independent of p53 by impairing the GSH/ROS balance. Blood 2014; 124 (10): 1626–1636. doi: 10.1182/blood-2014-01-548800.

34. Russo D, Ottaggio L, Foggetti G et al. PRIMA-1 induces autophagy in cancer cells carrying mutant or wild type p53. Biochim Biophys Acta 2013; 1833 (8): 1904–1913. doi: 10.1016/j.bbamcr.2013.03.020.

35. Lee K, Wang T, Paszczynski AJ et al. Expression proteomics to p53 mutation reactivation with PRIMA-1 in breast cancer cells. Biochem Biophys Res Commun 2006; 349 (3): 1117–1124. doi: 10.1016/j.bbrc.2006.08.152.

36. Wang XZ, Lawson B, Brewer JW et al. Signals from the stressed endoplasmic reticulum induce C/EBP-homologous protein (CHOP/GADD153). Mol Cell Biol 1996; 16 (8): 4273–4280.

37. Murray-Zmijewski F, Lane DP, Bourdon JC. p53/ p63/p73 isoforms: an orchestra of isoforms to harmonise cell differentiation and response to stress. Cell Death Differ 2006; 13 (6): 962–972. doi: 10.1038/sj.cdd.4401914.

38. Orzol P, Holcakova J, Nekulova M et al. The diverse oncogenic and tumour suppressor roles of p63 and p73 in cancer: a review by cancer site. Histol Histopathol 2015; 30 (5): 503–521. doi: 10.14670/HH-30.503.

39. Shen J, van den Bogaard EH, Kouwenhoven EN et al. APR-246/PRIMA-1 (MET) rescues epidermal differentiation in skin keratinocytes derived from EEC syndrome patients with p63 mutations. Proc Natl Acad Sci U S A 2013; 110 (6): 2157–2162. doi: 10.1073/pnas.1201993110.

40. Shalom-Feuerstein R, Serror L, Aberdam E et al. Impaired epithelial differentiation of induced pluripotent stem cells from ectodermal dysplasia-related patients is rescued by the small compound APR-246/PRIMA-1MET. Proc Natl Acad Sci U S A 2013; 110 (6): 2152–2156. doi: 10.1073/pnas.1201753109.

41. Rökaeus N, Shen J, Eckhardt I et al. PRIMA-1 (MET) /APR-246 targets mutant forms of p53 family members p63 and p73. Oncogene 2010; 29 (49): 6442–6451. doi: 10.1038/onc.2010.382.

42. Saha MN, Jiang H, Yang Y et al. PRIMA-1Met/APR-246 displays high antitumor activity in multiple myeloma by induction of p73 and Noxa. Mol Cancer Ther 2013; 12 (11): 2331–2341. doi: 10.1158/1535-7163.MCT-12-1166.

43. Lambert JM, Gorzov P, Veprintsev DB et al. PRIMA-1 reactivates mutant p53 by covalent binding to the core domain. Cancer Cell 2009; 15 (5): 376–388. doi: 10.1016/j.ccr.2009.03.003.

44. Perdrix A, Najem A, Saussez S et al. PRIMA-1 and PRIMA-1 (Met) (APR-246): from mutant/wild type p53 reactivation to unexpected mechanisms underlying their potent anti-tumor effect in combinatorial therapies. Cancers (Basel) 2017; 9 (12): pii: E172. doi: 10.3390/cancers9120172.

45. Nahi H, Lehmann S, Mollgard L et al. Effects of PRIMA-1 on chronic lymphocytic leukaemia cells with and without hemizygous p53 deletion. Br J Haematol 2004; 127 (3): 285–291. doi: 10.1111/j.1365-2141.2004.05210.x.

46. Roh JL, Kang SK, Minn I et al. p53-Reactivating small molecules induce apoptosis and enhance chemotherapeutic cytotoxicity in head and neck squamous cell carcinoma. Oral Oncol 2011; 47 (1): 8–15. doi: 10.1016/j.oraloncology.2010.10.011.

47. Mohell N, Alfredsson J, Fransson A et al. APR-246 overcomes resistance to cisplatin and doxorubicin in ovarian cancer cells. Cell Death Dis 2015; 6: e1794. doi: 10.1038/cddis.2015.143.

48. Fransson A, Glaessgen D, Alfredsson J et al. Strong synergy with APR-246 and DNA-damaging drugs in primary cancer cells from patients with TP53 mutant high-grade serous ovarian cancer. J Ovarian Res 2016; 9 (1): 27. doi: 10.1186/s13048-016-0239-6.

49. Izetti P, Hautefeuille A, Abujamra AL et al. PRIMA-1, a mutant p53 reactivator, induces apoptosis and enhances chemotherapeutic cytotoxicity in pancreatic cancer cell lines. Invest New Drugs 2014; 32 (5): 783–794. doi: 10.1007/s10637-014-0090-9.

50. Messina RL, Sanfilippo M, Vella V et al. Reactivation of p53 mutants by prima-1 [corrected] in thyroid cancer cells. Int J Cancer 2012; 130 (10): 2259–2270. doi: 10.1002/ijc.26228.

51. Deben C, Lardon F, Wouters A et al. APR-246 (PRIMA-1 (MET)) strongly synergizes with AZD2281 (olaparib) induced PARP inhibition to induce apoptosis in non-small cell lung cancer cell lines. Cancer Lett 2016; 375 (2): 313–322. doi: 10.1016/j.canlet.2016.03. 017.

52. Synnott NC, Murray A, McGowan PM et al. Mutant p53: a novel target for the treatment of patients with triple-negative breast cancer? Int J Cancer 2017; 140 (1): 234–246. doi: 10.1002/ijc.30425.

53. Arenbergerova M, Puzanov I. BRAF mutation: a novel approach in targeted melanoma therapy. Klin Onkol 2012; 25 (5): 323–328.

54. Davies H, Bignell GR, Cox C et al. Mutations of the BRAF gene in human cancer. Nature 2002; 417 (6892): 949–954. doi: 10.1038/nature00766.

55. Krayem M, Journe F, Wiedig M et al. p53 Reactivation by PRIMA-1 (Met) (APR-246) sensitises (V600E/K) BRAF melanoma to vemurafenib. Eur J Cancer 2016; 55: 98–110. doi: 10.1016/j.ejca.2015.12.002.

56. Lehmann S, Bykov VJ, Ali D et al. Targeting p53 in vivo: a first-in-human study with p53-targeting compound APR-246 in refractory hematologic malignancies and prostate cancer. J Clin Oncol 2012; 30 (29): 3633–3639. doi: 10.1200/JCO.2011.40.7783.