Acquisition of a single EZH2 D1 domain mutation confers acquired resistance to EZH2-targeted inhibitors

Oncotarget

Volumn 6, Issue 32, 2015, Pages 32646-32655

  Baker, Theresa ^a   Nerle, Sujata ^a   Pritchard, Justin ^a   Zhao, Boyang ^a   Rivera, Victor M ^a   Garner, Andrew ^a   Gonzalvez, Francois ^a  

^a ARIAD PHARMACEUTICALS INC   (United States)

Author keywords

Cancer; Drug resistance; Epigenetics; EZH2; Mutation

Indexed keywords

CABOTEGRAVIR; HISTONE METHYLTRANSFERASE; POLYCOMB REPRESSIVE COMPLEX 2; TAZEMETOSTAT; TRANSCRIPTION FACTOR EZH2; ANTINEOPLASTIC AGENT; BENZAMIDE DERIVATIVE; EED PROTEIN, HUMAN; ENZYME INHIBITOR; EPZ-6438; EZH2 PROTEIN, HUMAN; GSK126; INDOLE DERIVATIVE; PROTEIN BINDING; PYRIDONE DERIVATIVE; SUZ12 PROTEIN, HUMAN;

ALLELE; ARTICLE; CATALYSIS; CONTROLLED STUDY; DRUG BINDING; DRUG RESISTANCE; DRUG SENSITIVITY; DRUG TARGETING; ENZYME ACTIVITY; EZH2 GENE; GENE; HUMAN; HUMAN CELL; MISSENSE MUTATION; NEXT GENERATION SEQUENCING; PROTEIN DOMAIN; VALIDATION STUDY; ANTAGONISTS AND INHIBITORS; DOSE RESPONSE; ENZYMOLOGY; GENETIC TRANSFECTION; GENETICS; HEK293 CELL LINE; METABOLISM; MOLECULARLY TARGETED THERAPY; MUTATION; NEOPLASMS; PATHOLOGY; PROTEIN TERTIARY STRUCTURE; RNA INTERFERENCE; TIME FACTOR;

ANTINEOPLASTIC AGENTS; BENZAMIDES; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG RESISTANCE, NEOPLASM; ENHANCER OF ZESTE HOMOLOG 2 PROTEIN; ENZYME INHIBITORS; HEK293 CELLS; HUMANS; INDOLES; MOLECULAR TARGETED THERAPY; MUTATION; NEOPLASMS; POLYCOMB REPRESSIVE COMPLEX 2; PROTEIN BINDING; PROTEIN STRUCTURE, TERTIARY; PYRIDONES; RNA INTERFERENCE; TIME FACTORS; TRANSFECTION;

EID: 84946029686     PISSN: None     EISSN: 19492553     Source Type: Journal    
DOI: 10.18632/oncotarget.5066     Document Type: Article

References (31)

1. Kleer CG, Cao Q, Varambally S, Shen R, Ota I, Tomlins SA, Ghosh D, Sewalt RG, Otte AP, Hayes DF, Sabel MS, Livant D, Weiss SJ, et al. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc Natl Acad Sci U S A. 2003; 100:11606-11611.
2. Varambally S, Dhanasekaran SM, Zhou M, Barrette TR, Kumar-Sinha C, Sanda MG, Ghosh D, Pienta KJ, Sewalt RG, Otte AP, Rubin MA, Chinnaiyan AM. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature. 2002; 419:624-629.
3. Wagener N, Macher-Goeppinger S, Pritsch M, Husing J, Hoppe-Seyler K, Schirmacher P, Pfitzenmaier J, Haferkamp A, Hoppe-Seyler F, Hohenfellner M. Enhancer of zeste homolog 2 (EZH2) expression is an independent prognostic factor in renal cell carcinoma. BMC Cancer. 2010; 10:524.
4. Bitler BG, Aird KM, Garipov A, Li H, Amatangelo M, Kossenkov AV, Schultz DC, Liu Q, Shih Ie M, ConejoGarcia JR, Speicher DW, Zhang R. Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1Amutated cancers. Nat Med. 2015; 21:231-238.
5. Knutson SK, Warholic NM, Wigle TJ, Klaus CR, Allain CJ, Raimondi A, Porter Scott M, Chesworth R, Moyer MP, Copeland RA, Richon VM, Pollock RM, Kuntz KW, et al. Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. Proc Natl Acad Sci U S A. 2013; 110:7922-7927.
6. Bodor C, Grossmann V, Popov N, Okosun J, O'Riain C, Tan K, Marzec J, Araf S, Wang J, Lee AM, Clear A, Montoto S, Matthews J, et al. EZH2 mutations are frequent and represent an early event in follicular lymphoma. Blood. 2013; 122:3165-3168.
7. McCabe MT, Graves AP, Ganji G, Diaz E, Halsey WS, Jiang Y, Smitheman KN, Ott HM, Pappalardi MB, Allen KE, Chen SB, Della Pietra A 3rd, Dul E, et al. Mutation of A677 in histone methyltransferase EZH2 in human B-cell lymphoma promotes hypertrimethylation of histone H3 on lysine 27 (H3K27). Proc Natl Acad Sci U S A. 2012; 109:2989-2994.
8. Morin RD, Johnson NA, Severson TM, Mungall AJ, An J, Goya R, Paul JE, Boyle M, Woolcock BW, Kuchenbauer F, Yap D, Humphries RK, Griffith OL, et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet. 2010; 42:181-185.
9. Ryan RJ, Nitta M, Borger D, Zukerberg LR, Ferry JA, Harris NL, Iafrate AJ, Bernstein BE, Sohani AR, Le LP. EZH2 codon 641 mutations are common in BCL2-rearranged germinal center B cell lymphomas. PLoS One. 2011; 6:e28585.
10. Swalm BM, Knutson SK, Warholic NM, Jin L, Kuntz KW, Keilhack H, Smith JJ, Pollock RM, Moyer MP, Scott MP, Copeland RA, Wigle TJ. Reaction Coupling between Wild-Type and Disease-Associated Mutant EZH2. ACS Chem Biol. 2014; 9:2459-2464.
11. Garapaty-Rao S, Nasveschuk C, Gagnon A, Chan EY, Sandy P, Busby J, Balasubramanian S, Campbell R, Zhao F, Bergeron L, Audia JE, Albrecht BK, Harmange JC, et al. Identification of EZH2 and EZH1 small molecule inhibitors with selective impact on diffuse large B cell lymphoma cell growth. Chem Biol. 2013; 20:1329-1339.
12. Knutson SK, Wigle TJ, Warholic NM, Sneeringer CJ, Allain CJ, Klaus CR, Sacks JD, Raimondi A, Majer CR, Song J, Scott MP, Jin L, Smith JJ, et al. A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat Chem Biol. 2012; 8:890-896.
13. McCabe MT, Ott HM, Ganji G, Korenchuk S, Thompson C, Van Aller GS, Liu Y, Graves AP, Della Pietra A 3rd, Diaz E, LaFrance LV, Mellinger M, Duquenne C, et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature. 2012; 492:108-112.
14. Antonysamy S, Condon B, Druzina Z, Bonanno JB, Gheyi T, Zhang F, MacEwan I, Zhang A, Ashok S, Rodgers L, Russell M, Gately Luz J. Structural context of disease-associated mutations and putative mechanism of autoinhibition revealed by X-ray crystallographic analysis of the EZH2-SET domain. PLoS One. 2013; 8:e84147.
15. Wu H, Zeng H, Dong A, Li F, He H, Senisterra G, Seitova A, Duan S, Brown PJ, Vedadi M, Arrowsmith CH, Schapira M. Structure of the catalytic domain of EZH2 reveals conformational plasticity in cofactor and substrate binding sites and explains oncogenic mutations. PLoS One. 2013; 8:e83737.
16. Knutson SK, Kawano S, Minoshima Y, Warholic NM, Huang KC, Xiao Y, Kadowaki T, Uesugi M, Kuznetsov G, Kumar N, Wigle TJ, Klaus CR, Allain CJ, et al. Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-Hodgkin lymphoma. Mol Cancer Ther. 2014; 13:842-854.
17. Epizyme. Cowen and Company 35th Annual Healthcare Conference; 2015.
18. O'Hare T, Eide CA, Deininger MW. New Bcr-Abl inhibitors in chronic myeloid leukemia: keeping resistance in check. Expert Opin Investig Drugs. 2008; 17:865-878.
19. Lackner MR, Wilson TR, Settleman J. Mechanisms of acquired resistance to targeted cancer therapies. Future Oncol. 2012; 8:999-1014.
20. Garraway LA, Janne PA. Circumventing cancer drug resistance in the era of personalized medicine. Cancer Discov. 2012; 2:214-226.
21. O'Hare T, Zabriskie MS, Eiring AM, Deininger MW. Pushing the limits of targeted therapy in chronic myeloid leukaemia. Nat Rev Cancer. 2012; 12:513-526.
22. Gainor JF, Shaw AT. Emerging paradigms in the development of resistance to tyrosine kinase inhibitors in lung cancer. J Clin Oncol. 2013; 31:3987-3996.
23. Arteaga CL, Engelman JA. ERBB receptors: from oncogene discovery to basic science to mechanism-based cancer therapeutics. Cancer Cell. 2014; 25:282-303.
24. Kim E, Kim M, Woo DH, Shin Y, Shin J, Chang N, Oh YT, Kim H, Rheey J, Nakano I, Lee C, Joo KM, Rich JN, et al. Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells. Cancer Cell. 2013; 23:839-852.
25. Vire E, Brenner C, Deplus R, Blanchon L, Fraga M, Didelot C, Morey L, Van Eynde A, Bernard D, Vanderwinden JM, Bollen M, Esteller M, Di Croce L, et al. The Polycomb group protein EZH2 directly controls DNA methylation. Nature. 2006; 439:871-874.
26. Bradley WD, Arora S, Busby J, Balasubramanian S, Gehling VS, Nasveschuk CG, Vaswani RG, Yuan CC, Hatton C, Zhao F, Williamson KE, Iyer P, Mendez J, et al. EZH2 inhibitor efficacy in non-Hodgkin's lymphoma does not require suppression of H3K27 monomethylation. Chem Biol. 2014; 21:1463-1475.
27. Gibaja V, Shen F, Harari J, Korn J, Ruddy D, Saenz-Vash V, Zhai H, Rejtar T, Paris CG, Yu Z, Lira M, King D, Qi W, et al. Development of secondary mutations in wild-type and mutant EZH2 alleles cooperates to confer resistance to EZH2 inhibitors. Oncogene. 2015. doi: 10.1038/onc.2015.114.
28. Bradeen HA, Eide CA, O'Hare T, Johnson KJ, Willis SG, Lee FY, Druker BJ, Deininger MW. Comparison of imatinib mesylate, dasatinib (BMS-354825), and nilotinib (AMN107) in an N-ethyl-N-nitrosourea (ENU)-based mutagenesis screen: high efficacy of drug combinations. Blood. 2006; 108:2332-2338.
29. Zhou W, Ercan D, Chen L, Yun CH, Li D, Capelletti M, Cortot AB, Chirieac L, Iacob RE, Padera R, Engen JR, Wong KK, Eck MJ, et al. Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. Nature. 2009; 462:1070-1074.
30. Zhang S, Wang F, Keats J, Zhu X, Ning Y, Wardwell SD, Moran L, Mohemmad QK, Anjum R, Wang Y, Narasimhan NI, Dalgarno D, Shakespeare WC, et al. Crizotinib-resistant mutants of EML4-ALK identified through an accelerated mutagenesis screen. Chem Biol Drug Des. 2011; 78:999-1005.
31. Kim W, Bird GH, NeffT, Guo G, Kerenyi MA, Walensky LD, Orkin SH. Targeted disruption of the EZH2-EED complex inhibits EZH2-dependent cancer. Nat Chem Biol. 2013; 9:643-650.