DOI QR코드

DOI QR Code

Synergistic Inhibition of Burkitt's Lymphoma with Combined Ibrutinib and Lapatinib Treatment

Ibrutinib과 Lapatinib 병용 치료에 의한 버킷림프종의 상호 작용적 억제

  • Chae-Eun YANG (Department of Biomedical Laboratory Science, Inje University) ;
  • Se Been KIM (Department of Biomedical Laboratory Science, Inje University) ;
  • Yurim JEONG (Department of Biomedical Laboratory Science, Inje University) ;
  • Jung-Yeon LIM (Department of Biomedical Laboratory Science, Inje University)
  • Received : 2023.11.10
  • Accepted : 2023.12.10
  • Published : 2023.12.31

Abstract

Burkitt's lymphoma is a distinct subtype of non-Hodgkin's lymphoma originating from B-cells that is notorious for its aggressive growth and association with immune system impairments, potentially resulting in rapid and fatal outcomes if not addressed promptly. Optimizing the use of Food and Drug Administration-approved medications, such as combining known safe drugs, can lead to time and cost savings. This method holds promise in accelerating the progress of novel treatments, ultimately facilitating swifter access for patients. This study explores the potential of a dual-targeted therapeutic strategy, combining the bruton tyrosine kinase-targeting drug Ibrutinib and the epidermal growth factor receptor/human epidermal growth factor receptor-2-targeting drug Lapatinib. Ramos and Daudi cell lines, well-established models of Burkitt's lymphoma, were used to examine the impact of this combination therapy. The combination of Ibrutinib and Lapatinib inhibited cell proliferation more than using each drug individually. A combination treatment induced apoptosis and caused cell cycle arrest at the S and G2/M phases. This approach is multifaceted in its benefits. It enhances the efficiency of the drug development timeline and maximizes the utility of currently available resources, ensuring a more streamlined and resource-effective research process.

버킷 림프종(Burkitt's lymphoma)은 B-세포에서 발생하는 비호지킨 림프종의 한 형태로, 빠른 성장과 면역계 장애와 관련된 특성으로 인해 약물이 투여되지 않으면 생존율이 감소하거나 나쁜 예후로 이어질 수 있다. Food and Drug Administration (FDA) 승인된 약물의 최적 활용, 안전한 약물을 병용하는 방법은 시간과 비용 절감을 가능하게 한다. 이 접근법은 새로운 치료법 개발을 하기 보다는 기존에 FDA 승인된 약물을 적응증이 다른 환자에게 빠르게 접근할 수 있는 가능성을 제공한다. 이 연구는 BTK를 표적으로 하는 이브루티닙(Ibrutinib)과 EGFR/HER2를 표적으로 하는 라파티닙(Lapatinib) 병용 치료 전략의 잠재력을 확인하였다. 버킷 림프종의 잘 알려진 Ramos 및 Daudi 세포주가 이 연구에 활용되어 이 병합 치료의 영향을 밝히는 역할을 하였다. 이브루티닙과 라파티닙의 병용치료가 단일 약물 대비 세포 증식을 상당히 억제하는 것을 보여주었다. 또한 병용 치료가 세포 사멸을 유도하고 S 및 G2/M 단계에서 세포주기 중단을 유발하는 것을 관찰하였다. 이 접근법은 약물 개발 일정을 간소화하는 데 그치지 않고 이미 존재하는 자원의 활용을 극대화하는 것을 의미한다.

Keywords

Acknowledgement

This work was supported by grant from Inje University, 2023 (No. 20230017).

References

  1. Molyneux EM, Rochford R, Griffin B, Newton R, Jackson G, Menon G, et al. Burkitt's lymphoma. Lancet. 2012;379:1234-1244. https://doi.org/10.1016/s0140-6736(11)61177-x
  2. Lopez C, Burkhardt B, Chan JKC, Leoncini L, Mbulaiteye SM, Ogwang MD, et al. Burkitt lymphoma. Nat Rev Dis Primers. 2022;8:78. https://doi.org/10.1038/s41572-022-00404-3
  3. Salles G, Barrett M, Foa R, Maurer J, O'Brien S, Valente N, et al. Rituximab in B-cell hematologic malignancies: a review of 20 years of clinical experience. Adv Ther. 2017;34:2232-2273. https://doi.org/10.1007/s12325-017-0612-x
  4. Xue C, Wang X, Zhang L, Qu Q, Zhang Q, Jiang Y. Ibrutinib in B-cell lymphoma: single fighter might be enough? Cancer Cell Int. 2020;20:467. https://doi.org/10.1186/s12935-020-01518-y
  5. Kim E, Hurtz C, Koehrer S, Wang Z, Balasubramanian S, Chang BY, et al. Ibrutinib inhibits pre-BCR+ B-cell acute lymphoblastic leukemia progression by targeting BTK and BLK. Blood. 2017; 129:1155-1165. https://doi.org/10.1182/blood-2016-06-722900
  6. Johnston SR, Leary A. Lapatinib: a novel EGFR/HER2 tyrosine kinase inhibitor for cancer. Drugs Today (Barc). 2006;42:441-453. https://doi.org/10.1358/dot.2006.42.7.985637
  7. Opdam FL, Guchelaar HJ, Beijnen JH, Schellens JH. Lapatinib for advanced or metastatic breast cancer. Oncologist. 2012;17:536-542. https://doi.org/10.1634/theoncologist.2011-0461
  8. Chipuk JE, Kuwana T, Bouchier-Hayes L, Droin NM, Newmeyer DD, Schuler M, et al. Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science. 2004;303:1010-1014. https://doi.org/10.1126/science.1092734
  9. Basu A, Haldar S. The relationship between BcI2, Bax and p53: consequences for cell cycle progression and cell death. Mol Hum Reprod. 1998;4:1099-1109. https://doi.org/10.1093/molehr/4.12.1099
  10. Herman SE, Mustafa RZ, Gyamfi JA, Pittaluga S, Chang S, Chang B, et al. Ibrutinib inhibits BCR and NF-κB signaling and reduces tumor proliferation in tissue-resident cells of patients with CLL. Blood. 2014;123:3286-3295. https://doi.org/10.1182/blood-2014-02-548610
  11. Jeong Y, Kim SB, Yang CE, Yu MS, Choi WS, Jeon Y, et al. Overcoming the therapeutic limitations of EZH2 inhibitors in Burkitt's lymphoma: a comprehensive study on the combined effects of MS1943 and Ibrutinib. Front Oncol. 2023;13:1252658. https://doi.org/10.3389/fonc.2023.1252658
  12. Bilancia D, Rosati G, Dinota A, Germano D, Romano R, Manzione L. Lapatinib in breast cancer. Ann Oncol. 2007;18 Suppl 6:vi26-30. https://doi.org/10.1093/annonc/mdm220
  13. Kim SB, Yang CE, Jeong Y, Yu M, Choi WS, Lim JY, et al. Dual targeting of EZH2 degradation and EGFR/HER2 inhibition for enhanced efficacy against Burkitt's lymphoma. Cancers (Basel). 2023;15:4472. https://doi.org/10.3390/cancers15184472
  14. Los M, Mozoluk M, Ferrari D, Stepczynska A, Stroh C, Renz A, et al. Activation and caspase-mediated inhibition of PARP: a molecular switch between fibroblast necrosis and apoptosis in death receptor signaling. Mol Biol Cell. 2002;13:978-988. https://doi. org/10.1091/mbc.01-05-0272
  15. Taylor WR, Stark GR. Regulation of the G2/M transition by p53. Oncogene. 2001;20:1803-1815. https://doi.org/10.1038/sj.onc.1204252
  16. Srivastava N, Saxena AK. Caspase-3 activators as anticancer agents. Curr Protein Pept Sci. 2023;24:783-804. https://doi.org/10.2174/1389203724666230227115305
  17. Cui Q, Yu JH, Wu JN, Tashiro S, Onodera S, Minami M, et al. P53-mediated cell cycle arrest and apoptosis through a caspase-3- independent, but caspase-9-dependent pathway in oridonin-treated MCF-7 human breast cancer cells. Acta Pharmacol Sin. 2007;28:1057-1066. https://doi.org/10.1111/j.1745-7254.2007.00588.x
  18. Nair R, Roden DL, Teo WS, McFarland A, Junankar S, Ye S, et al. c-Myc and Her2 cooperate to drive a stem-like phenotype with poor prognosis in breast cancer. Oncogene. 2014;33:3992-4002. https://doi.org/10.1038/onc.2013.368
  19. Park C, Cha HJ, Lee H, Hwang-Bo H, Ji SY, Kim MY, et al. Induction of G2/M cell cycle arrest and apoptosis by Genistein in human bladder cancer T24 cells through inhibition of the ROS-dependent PI3k/Akt signal transduction pathway. Antioxidants (Basel). 2019;8:327. https://doi.org/10.3390/antiox8090327
  20. Xia W, Spector S, Hardy L, Zhao S, Saluk A, Alemane L, et al. Tumor selective G2/M cell cycle arrest and apoptosis of epithelial and hematological malignancies by BBL22, a benzazepine. Proc Natl Acad Sci U S A. 2000;97:7494-7499. https://doi.org/10.1073/pnas.97.13.7494