keyword
https://read.qxmd.com/read/38546787/mediator-kinase-inhibition-reverses-castration-resistance-of-advanced-prostate-cancer
#1
JOURNAL ARTICLE
Jing Li, Thomas A Hilimire, Liu Yueying, Lili Wang, Jiaxin Liang, Balázs Győrffy, Vitali Sikirzhytski, Hao Ji, Li Zhang, Chen Cheng, Xiaokai Ding, Kendall R Kerr, Charles E Dowling, Alexander A Chumanevich, Zachary T Mack, Gary P Schools, Chang-Uk Lim, Leigh Ellis, Xiaolin Zi, Donald C Porter, Eugenia V Broude, Campbell McInnes, George Wilding, Michael B Lilly, Igor B Roninson, Mengqian Chen
Mediator kinases CDK19 and CDK8, pleiotropic regulators of transcriptional reprogramming, are differentially regulated by androgen signaling but both kinases are upregulated in castration-resistant prostate cancer (CRPC). Genetic or pharmacological inhibition of CDK8 and CDK19 reverses the castration-resistant phenotype and restores the sensitivity of CRPC xenografts to androgen deprivation in vivo. Prolonged CDK8/19 inhibitor treatment combined with castration not only suppresses the growth of CRPC xenografts but also induces tumor regression and cures...
March 28, 2024: Journal of Clinical Investigation
https://read.qxmd.com/read/38542313/overexpression-of-rest-represses-the-epithelial-mesenchymal-transition-process-and-decreases-the-aggressiveness-of-prostate-cancer-cells
#2
JOURNAL ARTICLE
Sebastián Indo, Octavio Orellana-Serradell, María José Torres, Enrique A Castellón, Héctor R Contreras
The RE-1 silencing transcription factor (REST) is a repressor factor related to neuroendocrine prostate cancer (PCa) (NEPC), a poor prognostic stage mainly associated with castration-resistant PCa (CRPC). NEPC is associated with cell transdifferentiation and the epithelial-mesenchymal transition (EMT) in cells undergoing androgen deprivation therapy (ADT) and enzalutamide (ENZ). The effect of REST overexpression in the 22rv1 cell line (xenograft-derived prostate cancer) on EMT, migration, invasion, and the viability for ENZ was evaluated...
March 15, 2024: International Journal of Molecular Sciences
https://read.qxmd.com/read/38538093/safety-and-efficacy-of-snk01-autologous-natural-killer-cells-in-combination-with-cytotoxic-chemotherapy-and-or-cetuximab-after-failure-of-prior-tyrosine-kinase-inhibitor-in-non-small-cell-lung-cancer-non-clinical-mouse-model-and-phase-i-iia-clinical-study
#3
JOURNAL ARTICLE
Myeong Geun Choi, Gun Woo Son, Mi Young Choi, Jae Seob Jung, Jin Kyung Rho, Wonjun Ji, Byeong Gon Yoon, Jong-Min Jo, Yong Man Kim, Dae-Hyun Ko, Jae Cheol Lee, Chang-Min Choi
BACKGROUND: Choosing treatments for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) patients with osimertinib resistance is challenging. We evaluated the safety and efficacy of SNK01 (autologous natural killer (NK) cells) in combination with cytotoxic chemotherapy and/or cetuximab (an anti-EGFR monoclonal antibody) in treating EGFR-mutated NSCLC in this non-clinical and phase I/IIa clinical trial. METHODS: We developed a cell line-derived xenograft-humanized mouse model with an osimertinib-resistant lung cancer cell line...
March 27, 2024: Journal for Immunotherapy of Cancer
https://read.qxmd.com/read/38536921/glutamine-antagonist-drp-104-suppresses-tumor-growth-and-enhances-response-to-checkpoint-blockade-in-keap1-mutant-lung-cancer
#4
JOURNAL ARTICLE
Ray Pillai, Sarah E LeBoeuf, Yuan Hao, Connie New, Jenna L E Blum, Ali Rashidfarrokhi, Shih Ming Huang, Christian Bahamon, Warren L Wu, Burcu Karadal-Ferrena, Alberto Herrera, Ellie Ivanova, Michael Cross, Jozef P Bossowski, Hongyu Ding, Makiko Hayashi, Sahith Rajalingam, Triantafyllia Karakousi, Volkan I Sayin, Kamal M Khanna, Kwok-Kin Wong, Robert Wild, Aristotelis Tsirigos, John T Poirier, Charles M Rudin, Shawn M Davidson, Sergei B Koralov, Thales Papagiannakopoulos
Loss-of-function mutations in KEAP1 frequently occur in lung cancer and are associated with poor prognosis and resistance to standard of care treatment, highlighting the need for the development of targeted therapies. We previously showed that KEAP1 mutant tumors consume glutamine to support the metabolic rewiring associated with NRF2-dependent antioxidant production. Here, using preclinical patient-derived xenograft models and antigenic orthotopic lung cancer models, we show that the glutamine antagonist prodrug DRP-104 impairs the growth of KEAP1 mutant tumors...
March 29, 2024: Science Advances
https://read.qxmd.com/read/38534178/a-novel-inhibitor-of-poly-adp-r-ibose-polymerase-1-inhibits-proliferation-of-a-brca-deficient-breast-cancer-cell-line-via-the-dna-d-amage-a-ctivated-cgas-sting-pathway
#5
JOURNAL ARTICLE
Yonglong Jin, Lijie Wang, Chengxue Jin, Na Zhang, Shosei Shimizu, Wenjing Xiao, Chuanlong Guo, Xiguang Liu, Hongzong Si
Loss-of-function mutations in the Breast Cancer Susceptibility Gene (BRCA1 and BRCA2) are often detected in patients with breast cancer. Poly(ADP-ribose) polymerase-1 (PARP1) plays a key role in the repair of DNA strand breaks, and PARP inhibitors have been shown to induce highly selective killing of BRCA1/2-deficient tumor cells, a mechanism termed synthetic lethality. In our previous study, a novel PARP1 inhibitor─( E )-2-(2,3-dibromo-4,5-dimethoxybenzylidene)- N -(4-fluorophenyl) hydrazine-1-carbothioamide (4F-DDC)─was synthesized, which significantly inhibited PARP1 activity with an IC50 value of 82 ± 9 nM...
March 27, 2024: Chemical Research in Toxicology
https://read.qxmd.com/read/38533822/vascularized-tissue-on-mesh-assisted-platform-vt-map-a-novel-approach-for-diverse-organoid-size-culture-and-tailored-cancer-drug-response-analysis
#6
JOURNAL ARTICLE
Jungseub Lee, Sangmin Jung, Hye Kyoung Hong, Hyeonsu Jo, Stephen Rhee, Ye-Lin Jeong, Jihoon Ko, Yong Beom Cho, Noo Li Jeon
This study presents the vascularized tissue on mesh-assisted platform (VT-MAP), a novel microfluidic in vitro model that uses an open microfluidic principle for cultivating vascularized organoids. Addressing the gap in 3D high-throughput platforms for drug response analysis, the VT-MAP can host tumor clusters of various sizes, allowing for precise, size-dependent drug interaction assessments. Key features include capability for forming versatile co-culture conditions (EC, fibroblasts and colon cancer organoids) that enhance tumor organoid viability and a perfusable vessel network that ensures efficient drug delivery and maintenance of organoid health...
March 27, 2024: Lab on a Chip
https://read.qxmd.com/read/38532108/co-targeting-cd47-and-vegf-elicited-potent-anti-tumor-effects-in-gastric-cancer
#7
JOURNAL ARTICLE
Kaiqi Zhang, Yuan Xu, Xusheng Chang, Caili Xu, Wenjing Xue, Dan Ding, Mingming Nie, Hui Cai, Jun Xu, Lu Zhan, Jiangbo Han, Tiancai Cai, Dianwen Ju, Li Feng, Xuyao Zhang, Kai Yin
BACKGROUND: CD47, serving as an intrinsic immune checkpoint, has demonstrated efficacy as an anti-tumor target in hematologic malignancies. Nevertheless, the clinical relevance of CD47 in gastric cancer and its potential as a therapeutic target remains unclear. METHODS: The expression of CD47 in clinical gastric cancer tissues was assessed using immunohistochemistry and Western blot. Patient-derived cells were obtained from gastric cancer tissues and co-cultured with macrophages derived from human peripheral blood mononuclear cells...
March 27, 2024: Cancer Immunology, Immunotherapy: CII
https://read.qxmd.com/read/38531616/signature-reversion-of-three-disease-associated-gene-signatures-prioritizes-cancer-drug-repurposing-candidates
#8
JOURNAL ARTICLE
Jennifer L Fisher, Elizabeth J Wilk, Vishal H Oza, Sam E Gary, Timothy C Howton, Victoria L Flanary, Amanda D Clark, Anita B Hjelmeland, Brittany N Lasseigne
Drug repurposing is promising because approving a drug for a new indication requires fewer resources than approving a new drug. Signature reversion detects drug perturbations most inversely related to the disease-associated gene signature to identify drugs that may reverse that signature. We assessed the performance and biological relevance of three approaches for constructing disease-associated gene signatures (i.e., limma, DESeq2, and MultiPLIER) and prioritized the resulting drug repurposing candidates for four low-survival human cancers...
March 26, 2024: FEBS Open Bio
https://read.qxmd.com/read/38530115/pharmacological-characterization-of-sdx-7320-evexomostat-a-novel-methionine-aminopeptidase-type-2-inhibitor-with-anti-tumor-and-anti-metastatic-activity
#9
JOURNAL ARTICLE
Peter Cornelius, Benjamin A Mayes, John S Petersen, David J Turnquist, Pierre J Dufour, Andrew J Dannenberg, James M Shanahan, Bradley J Carver
Methionine aminopeptidase type 2 (MetAP2) is a ubiquitous, evolutionarily conserved metalloprotease fundamental to protein biosynthesis which catalyzes removal of the N-terminal methionine residue from nascent polypeptides. MetAP2 is an attractive target for cancer therapeutics based upon its over-expression in multiple human cancers, the importance of MetAP2-specific substrates whose biological activity may be altered following MetAP2 inhibition, and additionally, that MetAP2 was identified as the target for the anti-angiogenic natural product, fumagillin...
March 26, 2024: Molecular Cancer Therapeutics
https://read.qxmd.com/read/38529546/metformin-suppresses-both-pd-l1-expression-in-cancer-cells-and-cancer-induced-pd-1-expression-in-immune-cells-to-promote-antitumor-immunity
#10
JOURNAL ARTICLE
Su Hwan Park, Juheon Lee, Hye Jin Yun, Seok-Ho Kim, Jong-Ho Lee
BACKGROUND: Metformin, a drug prescribed for patients with type 2 diabetes, has potential efficacy in enhancing antitumor immunity; however, the detailed underlying mechanisms remain to be elucidated. Therefore, we aimed to identify the inhibitory molecular mechanisms of metformin on programmed death ligand 1 (PD-L1) expression in cancer cells and programmed death 1 (PD-1) expression in immune cells. METHODS: We employed a luciferase reporter assay, quantitative real-time PCR, immunoblotting analysis, immunoprecipitation and ubiquitylation assays, and a natural killer (NK) cell-mediated tumor cell cytotoxicity assay...
March 26, 2024: Annals of Laboratory Medicine
https://read.qxmd.com/read/38529509/overcoming-brain-derived-therapeutic-resistance-in-her2-breast-cancer-brain-metastasis
#11
Danyyl Ippolitov, Yi-Han Lin, Jeremy Spence, Aleksandra Glogowska, Thatchawan Thanasupawat, Jason Beiko, Marc R Del Bigio, Xin Xu, Amy Wang, Raul Calvo, Abhijeet Kapoor, Juan J Marugan, Mark J Henderson, Thomas Klonisch, Sabine Hombach-Klonisch
Brain metastasis of HER2+ breast cancer occurs in about 50% of all women with metastatic HER2+ breast cancer and confers poor prognosis for patients. Despite effective HER2-targeted treatments of peripheral HER2+ breast cancer with Trastuzumab +/-HER2 inhibitors, limited brain permeability renders these treatments inefficient for HER2+ breast cancer brain metastasis (BCBM). The scarcity of suitable patient-derived in-vivo models for HER2+ BCBM has compromised the study of molecular mechanisms that promote growth and therapeutic resistance in brain metastasis...
February 22, 2024: bioRxiv
https://read.qxmd.com/read/38520909/ex-vivo-drug-testing-of-patient-derived-lung-organoids-to-predict-treatment-responses-for-personalized-medicine
#12
REVIEW
Josephine A Taverna, Chia-Nung Hung, Madison Williams, Ryan Williams, Meizhen Chen, Samaneh Kamali, Vaishnavi Sambandam, Cheryl Hsiang-Ling Chiu, Pawel A Osmulski, Maria E Gaczynska, Daniel T DeArmond, Christine Gaspard, Maria Mancini, Meena Kusi, Abhishek N Pandya, Lina Song, Lingtao Jin, Paolo Schiavini, Chun-Liang Chen
Lung cancer is the leading cause of global cancer-related mortality resulting in ∼ 1.8 million deaths annually. Systemic, molecular targeted, and immune therapies have provided significant improvements of survival outcomes for patients. However, drug resistance usually arises and there is an urgent need for novel therapy screening and personalized medicine. 3D patient-derived organoid (PDO) models have emerged as a more effective and efficient alternative for ex vivo drug screening than 2D cell culture and patient-derived xenograft (PDX) models...
March 14, 2024: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://read.qxmd.com/read/38518121/discovery-of-novel-5-6-dihydro-4-h-pyrido-2-3-4-de-quinazoline-irreversible-inhibitors-targeting-both-wild-type-and-a775_g776insyvma-mutated-her2-kinases
#13
JOURNAL ARTICLE
Leifu Yang, Yaxin Li, Yunling Du, Yan Guo, Zhenke Guo, Baoxiu Liu, Jianglin Liu, Yanfei Liu, Hongdan Niu, Yueming Sun, Henglin Yan, Yajuan Yang, Shannan Yu, Yifan Zhang, Yuan Zhang, Kun Zheng, Nanqiao Zheng, Xiaoqing Zhang, Qiang Zhang, Liming Hu
HER2 mutations were seen in 4% of non-small-cell lung cancer (NSCLC) patients. Most of these mutations (90%) occur as an insertion mutation within the exon 20 frame, leading to the downstream activation of the PI3K-AKT and RAS/MAPK pathways. However, no targeted therapies have yet been approved worldwide. Here a novel series of highly potent HER2 inhibitors with a pyrido[2,3,4- de ]quinazoline core were designed and developed. The derivatives with the pyrido[2,3,4- de ]quinazoline core displayed superior efficacy of antiproliferation in BaF3 cells harboring HER2insYVMA mutation compared with afatinib and neratinib...
March 22, 2024: Journal of Medicinal Chemistry
https://read.qxmd.com/read/38517886/evolution-of-chromosome-arm-aberrations-in-breast-cancer-through-genetic-network-rewiring
#14
JOURNAL ARTICLE
Elena Kuzmin, Toby M Baker, Tom Lesluyes, Jean Monlong, Kento T Abe, Paula P Coelho, Michael Schwartz, Joseph Del Corpo, Dongmei Zou, Genevieve Morin, Alain Pacis, Yang Yang, Constanza Martinez, Jarrett Barber, Hellen Kuasne, Rui Li, Mathieu Bourgey, Anne-Marie Fortier, Peter G Davison, Atilla Omeroglu, Marie-Christine Guiot, Quaid Morris, Claudia L Kleinman, Sidong Huang, Anne-Claude Gingras, Jiannis Ragoussis, Guillaume Bourque, Peter Van Loo, Morag Park
The basal breast cancer subtype is enriched for triple-negative breast cancer (TNBC) and displays consistent large chromosomal deletions. Here, we characterize evolution and maintenance of chromosome 4p (chr4p) loss in basal breast cancer. Analysis of The Cancer Genome Atlas data shows recurrent deletion of chr4p in basal breast cancer. Phylogenetic analysis of a panel of 23 primary tumor/patient-derived xenograft basal breast cancers reveals early evolution of chr4p deletion. Mechanistically we show that chr4p loss is associated with enhanced proliferation...
March 21, 2024: Cell Reports
https://read.qxmd.com/read/38515951/erlotinib-combination-with-a-mitochondria-targeted-ubiquinone-effectively-suppresses-pancreatic-cancer-cell-survival
#15
JOURNAL ARTICLE
Pui-Yin Leung, Wenjing Chen, Anissa N Sari, Poojitha Sitaram, Pui-Kei Wu, Susan Tsai, Jong-In Park
BACKGROUND: Pancreatic cancer is a leading cause of cancer-related deaths. Increased activity of the epidermal growth factor receptor (EGFR) is often observed in pancreatic cancer, and the small molecule EGFR inhibitor erlotinib has been approved for pancreatic cancer therapy by the food and drug administration. Nevertheless, erlotinib alone is ineffective and should be combined with other drugs to improve therapeutic outcomes. We previously showed that certain receptor tyrosine kinase inhibitors can increase mitochondrial membrane potential (Δψm ), facilitate tumor cell uptake of Δψm -sensitive agents, disrupt mitochondrial homeostasis, and subsequently trigger tumor cell death...
February 21, 2024: World Journal of Gastroenterology: WJG
https://read.qxmd.com/read/38515278/prom2-overexpression-induces-metastatic-potential-through-epithelial-to-mesenchymal-transition-and-ferroptosis-resistance-in-human-cancers
#16
JOURNAL ARTICLE
Justine Paris, Claire Wilhelm, Celeste Lebbé, Mohammed Elmallah, Frédéric Pamoukdjian, Audrey Héraud, Guillaume Gapihan, Aurore Van De Walle, Van Nhan Tran, Diaddin Hamdan, Clara Allayous, Maxime Battistella, Emmanuel Van Glabeke, Kah Wai Lim, Christophe Leboeuf, Sébastien Roger, Géraldine Falgarone, Anh Tuan Phan, Guilhem Bousquet
INTRODUCTION: Despite considerable therapeutic advances in the last 20 years, metastatic cancers remain a major cause of death. We previously identified prominin-2 (PROM2) as a biomarker predictive of distant metastases and decreased survival, thus providing a promising bio-target. In this translational study, we set out to decipher the biological roles of PROM2 during the metastatic process and resistance to cell death, in particular for metastatic melanoma. METHODS AND RESULTS: Methods and results: We demonstrated that PROM2 overexpression was closely linked to an increased metastatic potential through the increase of epithelial-to-mesenchymal transition (EMT) marker expression and ferroptosis resistance...
March 2024: Clinical and Translational Medicine
https://read.qxmd.com/read/38515149/circhas2-activates-ccne2-to-promote-cell-proliferation-and-sensitizes-the-response-of-colorectal-cancer-to-anlotinib
#17
JOURNAL ARTICLE
Haosheng Li, Haoran Feng, Tao Zhang, Junwei Wu, Xiaonan Shen, Shuiyu Xu, Lianghui Xu, Shaodong Wang, Yaqi Zhang, Wenqing Jia, Xiaopin Ji, Xi Cheng, Ren Zhao
BACKGROUND: Tyrosine kinase inhibitors (TKIs) are crucial in the targeted treatment of advanced colorectal cancer (CRC). Anlotinib, a multi-target TKI, has previously been demonstrated to offer therapeutic benefits in previous studies. Circular RNAs (circRNAs) have been implicated in CRC progression and their unique structural stability serves as promising biomarkers. The detailed molecular mechanisms and specific biomarkers related to circRNAs in the era of targeted therapies, however, remain obscure...
March 21, 2024: Molecular Cancer
https://read.qxmd.com/read/38515107/factors-associated-with-engraftment-success-of-patient-derived-xenografts-of-breast-cancer
#18
JOURNAL ARTICLE
Jongwon Lee, GunHee Lee, Hye Seon Park, Byung-Kwan Jeong, Gyungyub Gong, Jae Ho Jeong, Hee Jin Lee
BACKGROUND: Patient-derived xenograft (PDX) models serve as a valuable tool for the preclinical evaluation of novel therapies. They closely replicate the genetic, phenotypic, and histopathological characteristics of primary breast tumors. Despite their promise, the rate of successful PDX engraftment is various in the literature. This study aimed to identify the key factors associated with successful PDX engraftment of primary breast cancer. METHODS: We integrated clinicopathological data with morphological attributes quantified using a trained artificial intelligence (AI) model to identify the principal factors affecting PDX engraftment...
March 21, 2024: Breast Cancer Research: BCR
https://read.qxmd.com/read/38514606/the-eif3h-hax1-axis-increases-raf-mek-erk-signaling-activity-to-promote-colorectal-cancer-progression
#19
JOURNAL ARTICLE
Huilin Jin, Xiaoling Huang, Qihao Pan, Ning Ma, Xiaoshan Xie, Yue Wei, Fenghai Yu, Weijie Wen, Boyu Zhang, Peng Zhang, Xijie Chen, Jie Wang, Ran-Yi Liu, Junzhong Lin, Xiangqi Meng, Mong-Hong Lee
Eukaryotic initiation translation factor 3 subunit h (EIF3H) plays critical roles in regulating translational initiation and predicts poor cancer prognosis, but the mechanism underlying EIF3H tumorigenesis remains to be further elucidated. Here, we report that EIF3H is overexpressed in colorectal cancer (CRC) and correlates with poor prognosis. Conditional Eif3h deletion suppresses colorectal tumorigenesis in AOM/DSS model. Mechanistically, EIF3H functions as a deubiquitinase for HAX1 and stabilizes HAX1 via antagonizing βTrCP-mediated ubiquitination, which enhances the interaction between RAF1, MEK1 and ERK1, thereby potentiating phosphorylation of ERK1/2...
March 21, 2024: Nature Communications
https://read.qxmd.com/read/38509064/combined-kras-mapk-pathway-inhibitors-and-her2-directed-drug-conjugate-is-efficacious-in-pancreatic-cancer
#20
JOURNAL ARTICLE
Ashenafi Bulle, Peng Liu, Kuljeet Seehra, Sapana Bansod, Yali Chen, Kiran Zahra, Vikas Somani, Iftikhar Ali Khawar, Hung-Po Chen, Paarth B Dodhiawala, Lin Li, Yutong Geng, Chia-Kuei Mo, Jay Mahsl, Li Ding, Ramaswamy Govindan, Sherri Davies, Jacqueline Mudd, William G Hawkins, Ryan C Fields, David G DeNardo, Deborah Knoerzer, Jason M Held, Patrick M Grierson, Andrea Wang-Gillam, Marianna B Ruzinova, Kian-Huat Lim
Targeting the mitogen-activated protein kinase (MAPK) cascade in pancreatic ductal adenocarcinoma (PDAC) remains clinically unsuccessful. We aim to develop a MAPK inhibitor-based therapeutic combination with strong preclinical efficacy. Utilizing a reverse-phase protein array, we observe rapid phospho-activation of human epidermal growth factor receptor 2 (HER2) in PDAC cells upon pharmacological MAPK inhibition. Mechanistically, MAPK inhibitors lead to swift proteasomal degradation of dual-specificity phosphatase 6 (DUSP6)...
March 20, 2024: Nature Communications
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