ITK inhibition induced in vitro and in vivo anti-tumor activity through downregulating TCR signaling pathway in malignant T cell lymphoma

Cancer Cell International
Yalu LiuJun Zhu

Abstract

Angioimmunoblastic T cell lymphoma (AITL) is a distinct subtype of peripheral T cell lymphoma and associated with poor outcomes. The activation status of T cell receptor (TCR) signaling has recently become a focus of attention in terms of the therapeutic targets. However, the molecular pathogenesis mechanisms and novel therapeutic targets are largely unknown. Antibodies specific to phosphorylated ZAP70, ITK and PLCγ1 were used to identify the activation status of intracellular proteins involved in TCR signaling in AITL patients. Malignant T cell lymphoma cells were transduced with a lentiviral construct containing ITK shRNA for cellular and functional assays. The antitumor effects of the selective ITK inhibitor BMS-509744 were determined in vitro and in vivo. Immunohistochemistry staining showed that more than half of the AITL patients (n = 38) exhibited continuously activated intracellular TCR signaling pathway. Patients positive for phosphorylated ITK showed a lower rate of complete response (20% vs. 75%, P = 0.004) and a shorter progression-free survival (5.17 months vs. 25.1 months, P = 0.022) than patients negative for phosphorylated ITK. Genetic and pharmacological cellular ITK inhibition significantly compromised the pro...Continue Reading

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Citations

Aug 19, 2020·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Kristina S LechnerBenno Weigmann
Jan 23, 2021·Expert Opinion on Drug Delivery·Andrew S MikhailBradford J Wood
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Mar 17, 2021·Journal of Orthopaedic Surgery and Research·Xinlei ChenPeng Xue
Aug 10, 2021·IScience·Samuel WeeksMobin Karimi
Oct 31, 2021·Experimental Dermatology·Gennie L ParkmanMartin McMahon

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Methods Mentioned

BETA
GTPase
exome sequencing
Assay
PCR
electrophoresis
flow cytometry
xenograft
transfection
xenografts
transgenic

Software Mentioned

Wheeler Aligner ( BWA )
muTect
ModFit LT
Burrows
SPSS
CalcuSyn

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