RGD Reference Report - Ibrutinib significantly inhibited Bruton's tyrosine kinase (BTK) phosphorylation,in-vitro proliferation and enhanced overall survival in a preclinical Burkitt lymphoma (BL) model.

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Ibrutinib significantly inhibited Bruton's tyrosine kinase (BTK) phosphorylation,in-vitro proliferation and enhanced overall survival in a preclinical Burkitt lymphoma (BL) model.
Authors:	Chu, Yaya Lee, Sanghoon Shah, Tishi Yin, Changhong Barth, Matthew Miles, Rodney R Ayello, Janet Morris, Erin Harrison, Lauren Van de Ven, Carmella Galardy, Paul Goldman, Stanton C Lim, Megan S Hermiston, Michelle McAllister-Lucas, Linda M Giulino-Roth, Lisa Perkins, Sherrie L Cairo, Mitchell S
Citation:	Chu Y, etal., Oncoimmunology. 2018 Oct 11;8(1):e1512455. doi: 10.1080/2162402X.2018.1512455. eCollection 2019.
RGD ID:	124715474
Pubmed:	PMID:30546948 (View Abstract at PubMed)
PMCID:	PMC6287791 (View Article at PubMed Central)
DOI:	DOI:10.1080/2162402X.2018.1512455 (Journal Full-text)
Pediatric and adult patients with recurrent/refractory Burkitt lymphoma (BL) continue to have poor outcomes, emphasizing the need for newer therapeutic agents. Bruton's tyrosine kinase (BTK) is activated following B-cell receptor stimulation and in part regulates normal B-cell development. Ibrutinib, a selective and irreversible BTK inhibitor, has been efficacious in chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), Waldenström's macroglobulinemia, and marginal zone lymphoma. In this study, we investigated the efficacy of ibrutinib alone and in selective adjuvant combinations against BL in-vitro and in a human BL xenografted immune-deficient NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mouse model. Our data demonstrated that phospho-BTK level was significantly reduced in BL cells treated with ibrutinib (p < 0.001). Moreover, we observed a significant decrease in cell proliferation as well as significant decrease in IC50 of ibrutinib in combination with dexamethasone, rituximab, obinutuzumab, carfilzomib, and doxorubicin (p < 0.001). In-vivo studies demonstrated ibrutinib treated mice had a significantly prolonged survival with median survival of mice following ibrutinib treatment (32 days) (24 days) (p < 0.02). In conclusion, our findings demonstrate the significant in-vitro and preclinical in-vivo effects of ibrutinib in BL. Based on our preclinical results in this investigation, there is an on-going clinical trial comparing overall survival in children and adolescents with relapsed/refractory BL treated with chemoimmunotherapy with or without ibrutinib (NCT02703272).

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
BTK	Human	Burkitt lymphoma	ameliorates	IMP		Human cell line in a mouse model	RGD
Btk	Rat	Burkitt lymphoma	ameliorates	ISO	BTK (Homo sapiens)	Human cell line in a mouse model	RGD
Btk	Mouse	Burkitt lymphoma	ameliorates	ISO	BTK (Homo sapiens)	Human cell line in a mouse model	RGD

Objects Annotated

Genes (Rattus norvegicus)

Btk (Bruton tyrosine kinase)

Genes (Mus musculus)

Btk (Bruton agammaglobulinemia tyrosine kinase)

Genes (Homo sapiens)

BTK (Bruton tyrosine kinase)

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Ibrutinib significantly inhibited Bruton's tyrosine kinase (BTK) phosphorylation,in-vitro proliferation and enhanced overall survival in a preclinical Burkitt lymphoma (BL) model.