Hu14.18K.322A Causes Direct Cell Cytotoxicity and Synergizes with Induction Chemotherapy in High-Risk Neuroblastoma

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2024 Jun 19

PMID 38893185

Authors

Maria Thomas

Thu Hien Nguyen

Jenny Drnevich

Amber M DSouza

Pedro A de Alarcon

Manu Gnanamony

Affiliations

Soon will be listed here.

Abstract

The disialoganglioside, GD2, is a promising therapeutic target due to its overexpression in certain tumors, particularly neuroblastoma (NB), with limited expression in normal tissues. Despite progress, the intricate mechanisms of action and the full spectrum of the direct cellular responses to anti-GD2 antibodies remain incompletely understood. In this study, we examined the direct cytotoxic effects of the humanized anti-GD2 antibody hu14.18K322A (hu14) on NB cell lines, by exploring the associated cell-death pathways. Additionally, we assessed the synergy between hu14 and conventional induction chemotherapy drugs. Our results revealed that hu14 treatment induced direct cytotoxic effects in CHLA15 and SK-N-BE1 cell lines, with a pronounced impact on proliferation and colony formation. Apoptosis emerged as the predominant cell-death pathway triggered by hu14. Furthermore, we saw a reduction in GD2 surface expression in response to hu14 treatment. Hu14 demonstrated synergy with induction chemotherapy drugs with alterations in GD2 expression. Our comprehensive investigation provides valuable insights into the multifaceted effects of hu14 on NB cells, shedding light on its direct cytotoxicity, cell-death pathways, and interactions with induction chemotherapy drugs. This study contributes to the evolving understanding of anti-GD2 antibody therapy and its potential synergies with conventional treatments in the context of NB.

References

Kowalczyk A, Gil M, Horwacik I, Odrowaz Z, Kozbor D, Rokita H . The GD2-specific 14G2a monoclonal antibody induces apoptosis and enhances cytotoxicity of chemotherapeutic drugs in IMR-32 human neuroblastoma cells. Cancer Lett. 2009; 281(2):171-82. DOI: 10.1016/j.canlet.2009.02.040. View

Dai J, Zhang C, Guo L, He H, Jiang K, Huang Y . A necroptotic-independent function of MLKL in regulating endothelial cell adhesion molecule expression. Cell Death Dis. 2020; 11(4):282. PMC: 7181788. DOI: 10.1038/s41419-020-2483-3. View

Troschke-Meurer S, Zumpe M, Meissner L, Siebert N, Grabarczyk P, Forkel H . Chemotherapeutics Used for High-Risk Neuroblastoma Therapy Improve the Efficacy of Anti-GD2 Antibody Dinutuximab Beta in Preclinical Spheroid Models. Cancers (Basel). 2023; 15(3). PMC: 9913527. DOI: 10.3390/cancers15030904. View

Choi M, Price D, Ryter S, Choi A . Necroptosis: a crucial pathogenic mediator of human disease. JCI Insight. 2019; 4(15). PMC: 6693822. DOI: 10.1172/jci.insight.128834. View

Schulz G, Cheresh D, Varki N, Yu A, Staffileno L, Reisfeld R . Detection of ganglioside GD2 in tumor tissues and sera of neuroblastoma patients. Cancer Res. 1984; 44(12 Pt 1):5914-20. View

Horwacik I, Rokita H . Modulation of interactions of neuroblastoma cell lines with extracellular matrix proteins affects their sensitivity to treatment with the anti-GD2 ganglioside antibody 14G2a. Int J Oncol. 2017; 50(5):1899-1914. DOI: 10.3892/ijo.2017.3959. View

Alborzinia H, Florez A, Kreth S, Bruckner L, Yildiz U, Gartlgruber M . MYCN mediates cysteine addiction and sensitizes neuroblastoma to ferroptosis. Nat Cancer. 2022; 3(4):471-485. PMC: 9050595. DOI: 10.1038/s43018-022-00355-4. View

Keyel M, Reynolds C . Spotlight on dinutuximab in the treatment of high-risk neuroblastoma: development and place in therapy. Biologics. 2019; 13:1-12. PMC: 6306059. DOI: 10.2147/BTT.S114530. View

Doronin I, Vishnyakova P, Kholodenko I, Ponomarev E, Ryazantsev D, Molotkovskaya I . Ganglioside GD2 in reception and transduction of cell death signal in tumor cells. BMC Cancer. 2014; 14:295. PMC: 4021548. DOI: 10.1186/1471-2407-14-295. View

10.

Philippova J, Shevchenko J, Sennikov S . GD2-targeting therapy: a comparative analysis of approaches and promising directions. Front Immunol. 2024; 15:1371345. PMC: 10979305. DOI: 10.3389/fimmu.2024.1371345. View

11.

Horwacik I, Durbas M, Boratyn E, Wegrzyn P, Rokita H . Targeting GD2 ganglioside and aurora A kinase as a dual strategy leading to cell death in cultures of human neuroblastoma cells. Cancer Lett. 2013; 341(2):248-64. DOI: 10.1016/j.canlet.2013.08.018. View

12.

Liu W, Ye L, Huang W, Guo L, Xu Z, Wu H . p62 links the autophagy pathway and the ubiqutin-proteasome system upon ubiquitinated protein degradation. Cell Mol Biol Lett. 2017; 21:29. PMC: 5415757. DOI: 10.1186/s11658-016-0031-z. View

13.

Minamoto T, Buschmann T, Habelhah H, Matusevich E, Tahara H, Harris C . Distinct pattern of p53 phosphorylation in human tumors. Oncogene. 2001; 20(26):3341-7. DOI: 10.1038/sj.onc.1204458. View

14.

Cochonneau D, Terme M, Michaud A, Dorvillius M, Gautier N, Frikeche J . Cell cycle arrest and apoptosis induced by O-acetyl-GD2-specific monoclonal antibody 8B6 inhibits tumor growth in vitro and in vivo. Cancer Lett. 2013; 333(2):194-204. DOI: 10.1016/j.canlet.2013.01.032. View

15.

Kroesen M, Bull C, Gielen P, Brok I, Armandari I, Wassink M . Anti-GD2 mAb and Vorinostat synergize in the treatment of neuroblastoma. Oncoimmunology. 2016; 5(6):e1164919. PMC: 4938306. DOI: 10.1080/2162402X.2016.1164919. View

16.

Higashimoto Y, Saito S, Tong X, Hong A, Sakaguchi K, Appella E . Human p53 is phosphorylated on serines 6 and 9 in response to DNA damage-inducing agents. J Biol Chem. 2000; 275(30):23199-203. DOI: 10.1074/jbc.M002674200. View

17.

Furman W, McCarville B, Shulkin B, Davidoff A, Krasin M, Hsu C . Improved Outcome in Children With Newly Diagnosed High-Risk Neuroblastoma Treated With Chemoimmunotherapy: Updated Results of a Phase II Study Using hu14.18K322A. J Clin Oncol. 2021; 40(4):335-344. PMC: 8797508. DOI: 10.1200/JCO.21.01375. View

18.

Soneson C, Love M, Robinson M . Differential analyses for RNA-seq: transcript-level estimates improve gene-level inferences. F1000Res. 2016; 4:1521. PMC: 4712774. DOI: 10.12688/f1000research.7563.2. View

19.

Julien S, Bobowski M, Steenackers A, Le Bourhis X, Delannoy P . How Do Gangliosides Regulate RTKs Signaling?. Cells. 2014; 2(4):751-67. PMC: 3972652. DOI: 10.3390/cells2040751. View

20.

Martens S, Bridelance J, Roelandt R, Vandenabeele P, Takahashi N . MLKL in cancer: more than a necroptosis regulator. Cell Death Differ. 2021; 28(6):1757-1772. PMC: 8184805. DOI: 10.1038/s41418-021-00785-0. View