Dual Targeting of EZH2 Degradation and EGFR/HER2 Inhibition for Enhanced Efficacy against Burkitt's Lymphoma

Se Been Kim; Chae-Eun Yang; Yurim Jeong; Minseo Yu; Wan-Su Choi; Jung-Yeon Lim; Youngwoo Jeon

doi:10.3390/cancers15184472

Dual Targeting of EZH2 Degradation and EGFR/HER2 Inhibition for Enhanced Efficacy against Burkitt's Lymphoma

Cancers (Basel). 2023 Sep 8;15(18):4472. doi: 10.3390/cancers15184472.

Authors

Se Been Kim^{1

2

3}, Chae-Eun Yang^{1

2

3}, Yurim Jeong^{1

2

3}, Minseo Yu^{1

2

3}, Wan-Su Choi^{1

4}, Jung-Yeon Lim^{1

2

3}, Youngwoo Jeon^{2

3

5}

Affiliations

¹ Department of Biomedical Laboratory Science, Inje University, Gimhae 50834, Republic of Korea.
² Lymphoma and Cell-Therapy Research Center, Yeouido St. Mary Hospital, School of Medicine, The Catholic University of Korea, Seoul 07345, Republic of Korea.
³ JL's Lymphoma Origins & Clinical Applications Lab (JL-LOCAL), The Catholic University of Korea, Seoul 07345, Republic of Korea.
⁴ Department of Digital Anti-Aging Health Care, Inje University, Gimhae 50834, Republic of Korea.
⁵ Department of Hematology, Yeouido St. Mary Hospital, School of Medicine, The Catholic University of Korea, Seoul 07345, Republic of Korea.

Abstract

EZH2, a histone methyltransferase, contributes significantly to cancer cell survival and proliferation. Although various EZH2 inhibitors have demonstrated promise in treating lymphoma, they have not fully managed to curb lymphoma cell proliferation despite effective reduction of the H3K27me3 mark. We used MS1943, an EZH2 selective degrader, which successfully diminishes EZH2 levels in lymphoma cells. Additionally, lapatinib, a dual inhibitor of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) tyrosine kinases, targets a receptor protein that regulates cell growth and division. The overexpression of this protein is often observed in lymphoma cells. Our study aims to combine these two therapeutic targets to stimulate apoptosis pathways and potentially suppress Burkitt's lymphoma cell survival and proliferation in a complementary and synergistic manner. We observed that a combination of MS1943 and lapatinib induced apoptosis in Daudi cells and caused cell cycle arrest at the S and G2/M phases in both Ramos and Daudi cells. This strategy, using a combination of MS1943 and lapatinib, presents a promising therapeutic approach for treating lymphoma and potentially Burkitt's lymphoma.

Keywords: EZH2; HER2/neu-EGFR; PROTAC; apoptosis; lymphoma.

Grants and funding

This research was funded by the National Research Foundation of Korea (NRF) grant number (No. NRF-2022R1F1A1061005) and grant funded by the Korea government (MSIT).