Hepatocellular carcinoma (HCC) stands as one of the most aggressively advancing and lethal malignancies. Sorafenib is presently endorsed as a primary therapy for advanced liver cancer, but its resistance presents a formidable challenge. Previous studies have implicated a connection between post-sorafenib discontinuation rebound and the development of drug resistance, yet the underlying mechanism remains elusive. In this study, we discerned that Sorafenib induced a senescent phenotype in HCC cells and caused a cleavage of ubiquitin-binding protein p62. Mechanistic studies establish that truncated p62 drives cellular senescence by promoting proteasome-dependent degradation of 4EBP1. Furthermore, truncated p62 induced specific ubiquitination of 4EBP1. Crucially, virtual drug screening uncovered that dacinostat inhibited cellular senescence by blocking sorafenib-induced p62 cleavage. In summary, our findings imply that truncated p62 from sorafenib cleavage promotes senescence via 4EBP1 degradation. The prevention of p62 cleavage could emerge as a crucial strategy for impeding the sorafenib-induced cellular senescence.

01 Apr 2024·iScience

Inference of drug off-target effects on cellular signaling using interactome-based deep learning

Article

Author: Lauffenburger, Douglas A ; Nilsson, Avlant ; Meimetis, Nikolaos

Many diseases emerge from dysregulated cellular signaling, and drugs are often designed to target specific signaling proteins. Off-target effects are, however, common and may ultimately result in failed clinical trials. Here we develop a computer model of the cell's transcriptional response to drugs for improved understanding of their mechanisms of action. The model is based on ensembles of artificial neural networks and simultaneously infers drug-target interactions and their downstream effects on intracellular signaling. With this, it predicts transcription factors' activities, while recovering known drug-target interactions and inferring many new ones, which we validate with an independent dataset. As a case study, we analyze the effects of the drug Lestaurtinib on downstream signaling. Alongside its intended target, FLT3, the model predicts an inhibition of CDK2 that enhances the downregulation of the cell cycle-critical transcription factor FOXM1. Our approach can therefore enhance our understanding of drug signaling for therapeutic design.

01 Mar 2023·International immunopharmacology

Pan-HDAC inhibitors augment IL2-induced proliferation of NK cells via the JAK2-STAT5B signaling pathway

Article

Author: Zong, Suyu ; Zhang, Yingchi ; Xiao, Jun ; Hu, Tianyuan ; Zheng, Jiarui ; Li, Long ; Chen, Xiaoli ; Lu, Yao ; Duan, Yongjuan

BACKGROUND:

Natural killer (NK) cells are a subtype of lymphocytes with the ability to quickly and efficiently identify and eliminate tumor cells. In the presence of IL2, NK cells can divide rapidly but in limited numbers. According to previous studies, in vivo treatment with histone deacetylase (HDAC) inhibitors did not impair NK-cell function. This study aimed to investigate the effect of HDAC inhibitors on NK-cell proliferation and the underlying regulatory mechanism.

METHODS:

NK92 cells, primary NK (pNK) cells, and CD19-CAR-NK92 cells were treated with low concentrations of pan-HDACi Dacinostat (Dac) and Panobinostat (Pan) in the presence of IL2, and Cell Counting Kit-8 (CCK8), 5-ethynyl-2'-deoxyuridine (EdU), and flow cytometry assays were used to assess cell proliferation and apoptosis. The expression of granzyme B was detected by immunofluorescence, and the expression of CD107a and NKG2D was determined by flow cytometry. The downstream regulatory genes were identified by RNA-seq, and the "JAK-STAT signaling pathway"- and "Cell cycle signaling pathway"-related genes were detected by real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis. The JAK2^V617F mouse model was constructed to simulate the upregulation of the JAK2 signaling pathway in vivo, and the NK proliferation was evaluated by flow cytometry. A tumor-bearing nude mouse model was constructed to determine the anti-tumor efficacy of NK92 cells following Dac treatment.

RESULTS:

In the presence of IL2, the proliferation rate of NK92 cells, pNK cells, and CD19-CAR-NK92 cells treated with pan-HDACi Dac and Pan at low nanomolar doses was significantly increased, although cell function was unaffected. Low doses of Dac upregulated the JAK-STAT signaling pathway and enhance the cell cycle via that pathway. In addition, the in vivo experiment in nude mice showed that the capacity of Dac treated NK92 cells to eliminate tumor cells was unaffected.

CONCLUSION:

Low nanomolar doses of Pan-HDACi enhanced IL2-induced NK cell proliferation without compromising the functioning of NK cells.

100 Deals associated with Dacinostat

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Phase 1	US	Novartis AG	-
Neoplasms	Phase 1	-	Novartis Pharma AG	-

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ASTRO2005	Not Applicable	Bronchogenic Carcinoma	-	NVP-LAQ824	eoylcejmmd(ghyyfrccfa) = utlaiuaztq xkxvlcplal (rwsvlcigiw, 3.2)	-	01 Oct 2005
ASTRO2005	Not Applicable	Bronchogenic Carcinoma	-	NVP-LAQ824 (3 Gy)	eoylcejmmd(ghyyfrccfa) = mslipupktb xkxvlcplal (rwsvlcigiw, 1.3)	-	01 Oct 2005
ASTRO2005	Not Applicable	Glioma	-	LAQ824	uahhnmfwsl(bnuykhaodi) = zncfubdybr xaqtbabpkd (pwzffbgpgs )	-	01 Oct 2005
ASCO2005	Phase 1	HR-positive/HER2-low Solid Tumors \| Hematologic Neoplasms	77	LAQ824	xvucinsjyv(vutcuiiqzc) = kvqefvtkkl fqrjqlxque (enjpzlieys ) View more	-	01 Jun 2005
ASCO2004	Phase 1	HR-positive/HER2-low Solid Tumors	28	LAQ824	uaxqmikkwu(frfvvuockz) = nlidjupycr eglebxncrz (obetypngin )	-	15 Jul 2004
ASCO2004	Phase 1	Hematologic Neoplasms	21	LAQ824	owppjgggvk(fkbcvvmvhx) = zjwajkknre kqriveafgd (qkqedmolsf ) View more	-	15 Jul 2004

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