Page 134 - D. Cancer biology

[D. Cancer biology-85]

Combination treatment with GSK126 and pomalidomide

induces B-cell differentiation and apoptosis in EZH2 gain-of-

function mutant diffuse large B-cell lymphoma

Sungryul Park¹˙²˙#, Seung-Hyun Jo¹˙²˙#, Jong-Hwan Kim³, Seon-Young Kim²˙³, Hyung Soo Kim⁴, Jae Du Ha⁵, Jong

Yeon Hwang⁵˙⁶, Myeong Youl Lee⁷, Jong Soon Kang⁷, Tae-Su Han⁸, Sung Goo Park¹˙², Byoung Chul Park¹˙²˙*,

Sunhong Kim¹˙²˙*, Jeong-Hoon Kim¹˙²˙*

¹Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of
Korea, ²KRIBB, School of Bioscience, Korea University of Science and Technology, Daejeon 34113, Republic of Korea, ³Personalized
Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea,
⁴Department of Chemistry, Korea University, Seoul 02841, Republic of Korea, ⁵Drug Discovery Division, Korea Research Institute of
Chemical Technology, Daejeon 305-606, Republic of Korea, ⁶Medicinal Chemistry and Pharmacology, Korea University of Science
and Technology, Daejeon 34113, Republic of Korea, ⁷7Laboratory Animal Resource Center, Korea Research Institute of Bioscience

and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea, ⁸Biotherapeutics Translational Research Center, Division of
Biomedical Science, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea

Enhancer of Zeste 2 Polycomb Repressive Complex 2 subunit (EZH2), the catalytic subunit of Polycomb repressive
complex 2 (PRC2), regulates genes involved in cell lineage and differentiation through methylating lysine 27 on
histone H3 (H3K27me3). Gain of-function mutations of EZH2 have been identified in various cancers, in particular,
diffuse large B-cell lymphoma (DLBCL), through genome-wide association studies and EZH2 depletion or
pharmacological inhibition shown to exert an anti-proliferative effect on cancer cells, both in vitro and in vivo. In

this study, a combination of pomalidomide and GSK126 synergistically inhibited growth of EZH2 gain-of-function
mutant DLBCL cells. Furthermore, this synergy appeared dependent on CRBN, a cellular receptor of pomalidomide,
but not degradation of IKAROS family Zinc Finger 1 (IKZF1) or IKAROS family Zinc Finger 3 (IKZF3). RNA sequencing
revealed that co-treatment with GSK126 and pomalidomide induced gene sets involved in B cell differentiation and
apoptosis. Synergistic growth inhibition and B cell differentiation were further validated in xenograft mouse models.
Our collective results provide a molecular basis for the mechanisms underlying the combined therapeutic effects of

PRC2 inhibitors and pomalidomide on EZH2-mutated DLBCL.