Inactivation of the CRL4-CDT2-SET8/p21 Ubiquitylation and Degradation Axis Underlies the Therapeutic Efficacy of Pevonedistat in Melanoma

Overview

Journal EBioMedicine

Specialty Biomedical Engineering

Date 2016 Jun 23

PMID 27333051

Citations 41

Authors

Mouadh Benamar

Fadila Guessous

Kangping Du

Patrick Corbett

Joseph Obeid

Daniel Gioeli

Craig L Slingluff Jr

Tarek Abbas

Affiliations

Soon will be listed here.

Abstract

Research In Context: The identification of new molecular targets and effective inhibitors is of utmost significance for the clinical management of melanoma. This study identifies CDT2, a substrate receptor for the CRL4 ubiquitin ligase, as a prognostic marker and therapeutic target in melanoma. CDT2 is required for melanoma cell proliferation and inhibition of CRL4(CDT2) by pevonedistat suppresses melanoma in vitro and in vivo through the induction of DNA rereplication and senescence through the stabilization of the CRL4(CDT2) substrates p21 and SET8. Pevonedistat also synergizes with vemurafenib in vivo and suppresses vemurafenib-resistant melanoma cells. These findings show a significant promise for targeting CRL4(CDT2) therapeutically.

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References

Flaherty K, Puzanov I, Kim K, Ribas A, McArthur G, Sosman J . Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010; 363(9):809-19. PMC: 3724529. DOI: 10.1056/NEJMoa1002011. View

Abbas T, Keaton M, Dutta A . Genomic instability in cancer. Cold Spring Harb Perspect Biol. 2013; 5(3):a012914. PMC: 3578360. DOI: 10.1101/cshperspect.a012914. View

Olivero M, Dettori D, Arena S, Zecchin D, Lantelme E, Di Renzo M . The stress phenotype makes cancer cells addicted to CDT2, a substrate receptor of the CRL4 ubiquitin ligase. Oncotarget. 2014; 5(15):5992-6002. PMC: 4171607. DOI: 10.18632/oncotarget.2042. View

Tardat M, Brustel J, Kirsh O, Lefevbre C, Callanan M, Sardet C . The histone H4 Lys 20 methyltransferase PR-Set7 regulates replication origins in mammalian cells. Nat Cell Biol. 2010; 12(11):1086-93. DOI: 10.1038/ncb2113. View

Kittlesen D, Thompson L, Gulden P, Skipper J, Colella T, Shabanowitz J . Human melanoma patients recognize an HLA-A1-restricted CTL epitope from tyrosinase containing two cysteine residues: implications for tumor vaccine development. J Immunol. 1998; 160(5):2099-106. View

Davies M, Samuels Y . Analysis of the genome to personalize therapy for melanoma. Oncogene. 2010; 29(41):5545-55. PMC: 3169242. DOI: 10.1038/onc.2010.323. View

Schotta G, Sengupta R, Kubicek S, Malin S, Kauer M, Callen E . A chromatin-wide transition to H4K20 monomethylation impairs genome integrity and programmed DNA rearrangements in the mouse. Genes Dev. 2008; 22(15):2048-61. PMC: 2492754. DOI: 10.1101/gad.476008. View

Balch C, Gershenwald J, Soong S, Thompson J, Atkins M, Byrd D . Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009; 27(36):6199-206. PMC: 2793035. DOI: 10.1200/JCO.2009.23.4799. View

Huntington J, Shields J, Der C, Wyatt C, Benbow U, Slingluff Jr C . Overexpression of collagenase 1 (MMP-1) is mediated by the ERK pathway in invasive melanoma cells: role of BRAF mutation and fibroblast growth factor signaling. J Biol Chem. 2004; 279(32):33168-76. DOI: 10.1074/jbc.M405102200. View

10.

Yamshchikov G, Thompson L, Ross W, Galavotti H, Aquila W, Deacon D . Analysis of a natural immune response against tumor antigens in a melanoma survivor: lessons applicable to clinical trial evaluations. Clin Cancer Res. 2001; 7(3 Suppl):909s-916s. View

11.

Jin J, Arias E, Chen J, Harper J, Walter J . A family of diverse Cul4-Ddb1-interacting proteins includes Cdt2, which is required for S phase destruction of the replication factor Cdt1. Mol Cell. 2006; 23(5):709-21. DOI: 10.1016/j.molcel.2006.08.010. View

12.

Slingluff Jr C, Cox A, Henderson R, Hunt D, Engelhard V . Recognition of human melanoma cells by HLA-A2.1-restricted cytotoxic T lymphocytes is mediated by at least six shared peptide epitopes. J Immunol. 1993; 150(7):2955-63. View

13.

Beck D, Burton A, Oda H, Ziegler-Birling C, Torres-Padilla M, Reinberg D . The role of PR-Set7 in replication licensing depends on Suv4-20h. Genes Dev. 2012; 26(23):2580-9. PMC: 3521623. DOI: 10.1101/gad.195636.112. View

14.

Sosman J, Kim K, Schuchter L, Gonzalez R, Pavlick A, Weber J . Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012; 366(8):707-14. PMC: 3724515. DOI: 10.1056/NEJMoa1112302. View

15.

Taylor B, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver B . Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010; 18(1):11-22. PMC: 3198787. DOI: 10.1016/j.ccr.2010.05.026. View

16.

Yamshchikov G, Mullins D, Chang C, Ogino T, Thompson L, Presley J . Sequential immune escape and shifting of T cell responses in a long-term survivor of melanoma. J Immunol. 2005; 174(11):6863-71. DOI: 10.4049/jimmunol.174.11.6863. View

17.

Le Poole I, Boissy R, Sarangarajan R, Chen J, Forristal J, Sheth P . PIG3V, an immortalized human vitiligo melanocyte cell line, expresses dilated endoplasmic reticulum. In Vitro Cell Dev Biol Anim. 2000; 36(5):309-19. DOI: 10.1290/1071-2690(2000)036<0309:PAIHVM>2.0.CO;2. View

18.

Tan M, Li H, Sun Y . Endothelial deletion of Sag/Rbx2/Roc2 E3 ubiquitin ligase causes embryonic lethality and blocks tumor angiogenesis. Oncogene. 2013; 33(44):5211-20. PMC: 4016996. DOI: 10.1038/onc.2013.473. View

19.

Talantov D, Mazumder A, Yu J, Briggs T, Jiang Y, Backus J . Novel genes associated with malignant melanoma but not benign melanocytic lesions. Clin Cancer Res. 2005; 11(20):7234-42. DOI: 10.1158/1078-0432.CCR-05-0683. View

20.

. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014; 511(7511):543-50. PMC: 4231481. DOI: 10.1038/nature13385. View