We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
ITK inhibition induced in vitro and in vivo anti-tumor activity through downregulating TCR signaling pathway in malignant T cell lymphoma.
- Authors
Liu, Yalu; Wang, Xiaogan; Deng, Lijuan; Ping, Lingyan; Shi, Yunfei; Zheng, Wen; Lin, Ningjing; Wang, Xiaopei; Tu, Meifeng; Xie, Yan; Liu, Weiping; Ying, Zhitao; Zhang, Chen; Pan, Zhengying; Wang, Xi; Ding, Ning; Song, Yuqin; Zhu, Jun
- Abstract
Background: 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. Methods: 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. Results: 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 proliferation, invasion and migration of malignant T cells. The selective ITK inhibitor BMS-509744 also induced the pro-apoptotic effects and G2/M phase cell cycle arrest in vitro and in vivo. Finally, inhibition of ITK synergistically enhanced the antitumor effect of vincristine and doxorubicin on malignant T cell lymphoma cell lines. Conclusions: Our findings suggest that ITK may be a novel candidate therapeutic target for the treatment of patients with ITK-expressing malignant T-cell lymphomas.
- Subjects
T cells; T cell receptors; VINCRISTINE
- Publication
Cancer Cell International, 2019, Vol 19, Issue 1, pN.PAG
- ISSN
1475-2867
- Publication type
Article
- DOI
10.1186/s12935-019-0754-9