Author: Chang, Jinhee ; Song, Yang ; Hoang, Tung ; Khan, Muhammad A. ; Lafargue, Audrey ; Chowdhury, Dipanwita D. ; Torres-Ayuso, Pedro ; Hann, Christine L. ; Carrieri, Francesca A. ; Tran, Phuoc T. ; Gabrielson, Kathleen L. ; Rezaee, Mohammad ; Connis, Nick ; Jagtap, Shreya ; Chan, Aaron ; Nguyen, Triet ; Shetty, Amol C. ; Brognard, John

AbstractMost patients with lung squamous cell carcinoma (LSCC) undergo chemotherapy, radiotherapy, and adjuvant immunotherapy for locally advanced disease. The efficacy of these treatments is still limited because of dose-limiting toxicity or locoregional recurrence. New combination approaches and targets such as actionable oncogenic drivers are needed to advance treatment options for patients with LSCC. Moreover, other options for chemotherapy-ineligible patients are limited. As such, there is a critical need for the development of selective and potent chemoradiosensitizers for locally advanced LSCC. In this study, we investigated inhibiting TRAF2- and NCK-interacting protein kinase (TNIK), which is amplified in 40% of patients with LSCC, as a strategy to sensitize LSCC tumors to chemotherapy and radiotherapy. Employing a range of human LSCC cell lines and the TNIK inhibitor NCB-0846, we investigated the potential of TNIK as a chemo- and radiosensitizing target with in vitro and in vivo preclinical models. The combination of NCB-0846 with cisplatin or etoposide was at best additive. Interestingly, pre-treating LSCC cells with NCB-0846 prior to ionizing radiation (IR) potentiated the cytotoxicity of IR in a TNIK-specific fashion. Characterization of the radiosensitization mechanism suggested that TNIK inhibition may impair the DNA damage response and promote mitotic catastrophe in irradiated cells. In a subcutaneous xenograft in vivo model, pretreatment with NCB-0846 significantly enhanced the efficacy of IR and caused elevated necrosis in TNIKhigh LK2 tumors but not TNIKlow KNS62 tumors. Overall, these results indicate that TNIK inhibition may be a promising strategy to increase the efficacy of radiotherapy in patients with LSCC with high TNIK expression.

01 May 2024·Genes & Diseases

The Traf2 and NcK interacting kinase inhibitor NCB-0846 suppresses seizure activity involving the decrease of GRIA1

Article

Author: Zhang, Yanke ; Dong, Zhifang ; Wang, Min ; Li, Qiubo ; Lv, Xinke ; Zhang, Hao ; Tian, Xin ; Kong, Qingxia ; Feng, Bangzhe ; Gu, Yixue

Epilepsy, one of the most common neurological disorders, is characterized by spontaneous recurrent seizures. Temporal lobe epilepsy (TLE) is one of the most common medically intractable seizure disorders. Traf2-and NcK-interacting kinase (TNIK) has recently attracted attention as a critical modulation target of many neurological and psychiatric disorders, but its role in epilepsy remains unclear. In this study, we hypothesized the involvement of TNIK in epilepsy and investigated TNIK expression in patients with intractable TLE and in a pilocarpine-induced rat model of epilepsy by western blotting, immunofluorescence, and immunohistochemistry. A pentylenetetrazole (PTZ)-induced epilepsy rat model was used to determine the effect of the TNIK inhibitor NCB-0846 on behavioral manifestations of epilepsy. Coimmunoprecipitation (Co-IP)/mass spectrometry (MS) was used to identify the potential mechanism. Through Co-IP, we detected and confirmed the main potential TNIK interactors. Subcellular fractionation was used to establish the effect of NCB-0846 on the expression of the main interactors in postsynaptic density (PSD) fractions. We found that TNIK was primarily located in neurons and decreased significantly in epilepsy model rats and TLE patients compared with controls. NCB-0846 delayed kindling progression and decreased seizure severity. Co-IP/MS identified 63 candidate TNIK interactors in rat hippocampi, notably CaMKII. Co-IP showed that TNIK might correlate with endogenous GRIA1, SYN2, PSD-95, CaMKIV, GABRG1, and GABRG2. In addition, the significant decrease in GRIA1 in hippocampal total lysate and PSDs after NCB-0846 treatment might help modify the progression of PTZ kindling. Our results suggest that TNIK contributes to epileptic pathology and is a potential antiepileptic drug target.

01 Apr 2024·JOURNAL OF BIOLOGICAL REGULATORS AND HOMEOSTATIC AGENTS

TRAF2 Drives the Proliferation and Metastasis of Oral Squamous Cell Carcinoma through the Mediation of the STAT3 Signaling Pathway

Author: Li, Ran ; Sun, Minglei ; Li, Guanghui

Oral squamous cell carcinoma (OSCC) stands as a prevalent malignant tumor worldwide, with its progression and metastasis representing primary contributors to therapeutic resistance and poor prognosis.Tumor necrosis factor receptorassocd. factor 2 (TRAF2) plays a pivotal role in various tumors.However, its precise function and underlying mechanisms in OSCC remain unclear.TRAF2 interacts with Signal Transducer and Activator of Transcription 3 (STAT3) in regulating cellular processes, including inflammation and immune responses.This study aimed to investigate the role of TRAF2 in OSCC proliferation and metastasis by mediating the STAT3 signaling pathway and its underlying mechanisms.The impact of TRAF2 overexpression, silencing, and STAT3 inhibition on OSCC cell proliferation, invasion, and morphol. alterations was evaluated using Cell Counting Kit-8 (CCK-8) assays, Transwell assays, and cytoskeleton staining, resp.Real-time quant. Polymerase Chain Reaction (PCR) and Western blot anal. were employed to investigate the impact of TRAF2 on the expression of key proteins in the STAT3 signaling pathway.TRAF2 overexpression upregulated phosphorylated Janus Kinase 2 (JAK2) and STAT3 levels (p < 0.05).Addnl., TRAF2 and STAT3 were co-localized within the cytoplasm.TRAF2 knockout suppressed STAT3 transcriptional processes, with notable reductions in mRNA levels of target genes E2F Transcription Factor 3 (E2F3), LIM Homeobox 1 (LHX1), Kinesin Family Member 18B (KIF18B), Spindle Pole Body Component 25 (SPC25), Nuclear Factor of Activated T cells 2 (NFATC2), Chromatin Accessibility Factor I A (CHAFIA), and Cytoskeleton-Associated Protein 2-Like (CKAP2L) (p < 0.05).Enhanced proliferation and invasion capacities were observed upon TRAF2 overexpression in OSCC cells, whereas TRAF2 silencing or STAT3 inhibition effectively reversed these effects.Addnl., TRAF2 overexpression induced significant alterations in cell morphol., which were reversed upon STAT3 silencing.Collectively, TRAF2 promotes OSCC cell proliferation and invasion by activating the STAT3 signaling pathway.This study reveals the pivotal role of TRAF2 in OSCC proliferation and metastasis through modulation of the STAT3 signaling pathway.Elevated TRAF2 and STAT3 expression correlates with enhanced proliferation and invasion capabilities of OSCC cells.The promotion of OSCC development by TRFA2 via STAT3 pathway activation underscores the potential of targeting the TRAF2/STAT3 axis as a therapeutic strategy for OSCC.These findings offer insights into OSCC mol. pathogenesis and lay a theor. foundation for developing novel treatment approaches.

100 Deals associated with NCB-0846

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Indication	Highest Phase	Country/Location	Organization	Date
Small Cell Lung Cancer	Preclinical	United States	The University of Texas MD Anderson Cancer Center	22 Mar 2024
Lung Cancer	Discovery	Japan	National Cancer Center Research Institute	01 Jul 2018
Lung Cancer	Discovery	-	Carna Biosciences, Inc.	01 Jul 2018

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