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Your search keyword '"Kinase activity"' showing total 3 results
3 results on '"Kinase activity"'

1. Low-dose triple drug combination targeting the PI3K/AKT/mTOR pathway and the MAPK pathway is an effective approach in ovarian clear cell carcinoma

Author

Mathilde Jalving, Arjan Kol, Anne van Wijngaarden, René Bernards, Steven de Jong, Gert Jan Meersma, Joseph J Caumanns, Ate G.J. van der Zee, G. Bea A. Wisman, Targeted Gynaecologic Oncology (TARGON), and Guided Treatment in Optimal Selected Cancer Patients (GUTS)

Subjects
0301 basic medicine, MAPK/ERK pathway, Cancer Research, Indazoles, Morpholines, Mice, Nude, Apoptosis, mTORC1, Mice, Phosphatidylinositol 3-Kinases, 03 medical and health sciences, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, Biomarkers, Tumor, Tumor Cells, Cultured, Animals, Humans, Medicine, Phosphorylation, Kinase activity, Protein Kinase Inhibitors, Protein kinase B, PI3K/AKT/mTOR pathway, Cell Proliferation, Ovarian Neoplasms, Benzoxazoles, Sulfonamides, Dose-Response Relationship, Drug, business.industry, Kinase, TOR Serine-Threonine Kinases, Cancer, Drug Synergism, medicine.disease, Xenograft Model Antitumor Assays, Gene Expression Regulation, Neoplastic, Pyrimidines, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Clear cell carcinoma, Cancer research, Benzimidazoles, Female, business, Proto-Oncogene Proteins c-akt, Adenocarcinoma, Clear Cell
Abstract

Advanced stage ovarian clear cell carcinoma (OCCC) is poorly responsive to platinum-based chemotherapy and has an unfavorable prognosis. Previous studies revealed heterogeneous mutations in PI3K/AKT/mTOR and MAPK pathway nodules converging in mTORC1/2 activation. Here, we aimed to identify an effective low-dose combination of PI3K/AKT/mTOR pathway and MAPK pathway inhibitors simultaneously targeting key kinases in OCCC to preclude single-inhibitor initiated pathway rewiring and limit toxicity. Small molecule inhibitors of mTORC1/2, PI3K and MEK1/2 were combined at monotherapy IC20 doses in a panel of genetically diverse OCCC cell lines (n = 7) to determine an optimal low-dose combination. The IC20 dose triple combination reduced kinase activity in PI3K/AKT/mTOR and MAPK pathways, prevented single-inhibitor induced feedback mechanisms and inhibited short and long-term proliferation in all seven cell lines. Finally, this low-dose triple drug combination treatment significantly reduced tumor growth in two genetically characterized OCCC patient-derived xenograft (PDX) models without resulting in weight loss in these mice. The effectiveness and tolerability of this combined therapy in PDX models warrants clinical exploration of this treatment strategy for OCCC and might be applicable to other cancer types with a similar genetic background.

Published
2019

2. Inhibition of mutant KrasG12D-initiated murine pancreatic carcinoma growth by a dual c-Raf and soluble epoxide hydrolase inhibitor t-CUPM.

Author

Liao, Jie, Hwang, Sung Hee, Li, Haonan, Yang, Yihe, Yang, Jun, Wecksler, Aaron T, Liu, Jun-Yan, Hammock, Bruce D, and Yang, Guang-Yu

Subjects
Cell Line, Tumor, Animals, Mice, Inbred C57BL, Mice, Mutant Strains, Carcinoma, Pancreatic Ductal, Pancreatic Neoplasms, Genetic Predisposition to Disease, Benzoates, Urea, Phenylurea Compounds, Niacinamide, Epoxide Hydrolases, Proto-Oncogene Proteins c-raf, Extracellular Signal-Regulated MAP Kinases, Antineoplastic Agents, Protein Kinase Inhibitors, Tumor Burden, Administration, Oral, Signal Transduction, Cell Proliferation, Phosphorylation, Dose-Response Relationship, Drug, Phenotype, Mutation, Genes, ras, Male, Oxylipins, Sorafenib, Growth inhibition, Pancreatic carcinoma, Soluble epoxide hydrolase, c-Raf, Pancreatic Cancer, Rare Diseases, Cancer, Digestive Diseases, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

Mutant Kras and chronic pancreatitis are the most common pathological events involved in human pancreatic cancer. It has been demonstrated that c-Raf is responsible for transmitting signals from mutant Ras to its downstream signals including MEK-ERK and for initiating carcinogenesis. The soluble epoxide hydrolase (sEH), a pro-inflammatory enzyme, generally inactivates anti-inflammatory and anti-pain epoxyeicosatrienoic acids (EETs). Herein, we have synthesized a novel compound of trans-4-{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-ureido]-cyclohexyloxy}-pyridine-2-carboxylic acid methylamide (t-CUPM) via modifying the central phenyl ring of sorafenib and confirmed its dual inhibition of sEH and c-Raf by recombinant kinase activity assay. Pharmacokinetic analysis revealed that oral dosing of t-CUPM resulted in higher blood levels than that of sorafenib throughout the complete time course (48 h). The effect of t-CUPM on the inhibition of mutant Kras(G12D)-initiated murine pancreatic cancer cell growth was determined using the mouse pancreatic carcinoma cell model obtained from LSL-Kras(G12D)/Pdx1-Cre mice and showed that t-CUPM significantly inhibited this murine pancreatic carcinoma cell growth both in vitro and in mice in vivo. Inhibition of mutant Kras-transmitted phosphorylations of cRAF/MEK/ERK was demonstrated in these pancreatic cancer cells using Western blot assay and immunohistochemical approach. Modulation of oxylipin profile, particularly increased EETs/DHET ratio by sEH inhibition, was observed in mice treated with t-CUPM. These results indicate that t-CUPM is a highly potential agent to treat pancreatic cancer via simultaneously targeting c-Raf and sEH.

Published
2016

3. HULC targets the IGF1R–PI3K-AKT axis in trans to promote breast cancer metastasis and cisplatin resistance

Author

Lei Zhou, Hui Li, Tingge Sun, Xue Wen, Chao Niu, Min Li, Wei Li, Andrew R. Hoffman, Ji-Fan Hu, and Jiuwei Cui

Subjects
Cancer Research, Apoptosis, Chromatin, Receptor, IGF Type 1, Gene Expression Regulation, Neoplastic, Histones, Mice, Phosphatidylinositol 3-Kinases, Oncology, Cell Line, Tumor, Animals, RNA, Long Noncoding, Cisplatin, Insulin-Like Growth Factor I, Neoplasm Recurrence, Local, Proto-Oncogene Proteins c-akt, Cell Proliferation
Abstract

Insulin-like growth factor I receptor (IGF1R) is frequently upregulated in breast cancer. Due to its intrinsic tyrosine kinase activity, aberrant activation of the IGF1R signaling axis may enhance tumor cell proliferation and cancer stemness, causing tumor relapse, metastasis and resistance to chemotherapy. We utilized a chromatin RNA in situ reverse transcription (CRIST) approach to characterize molecular factors that regulate the IGF1R network. We identified lncRNA HULC (Highly Upregulated in Liver Cancer) as a key trans-regulator of IGF1R in breast cancer cells. Loss of HULC suppressed the expression of IGF1R and the activation of its downstream PI3K/AKT pathway, while HULC overexpression activated the axis in breast cancer cells. Using a transcription-associated trap (RAT) assay, we demonstrated that HULC functioned as a nuclear lncRNA and epigenetically activated IGF1R by directly binding to the intragenic regulatory elements of the gene, orchestrating intrachromosomal interactions, and promoting histone H3K9 acetylation. The activated HULC-IGF1R/PI3K/AKT pathway mediated tumor resistance to cisplatin through the increased expression of cancer stemness markers, including NANOG, SOX2, OCT4, CD44 and ALDH1A1. In immunodeficient mice, stimulation of the HULC-IGF1R pathway promoted tumor metastasis. These data suggest that HULC may be a new epigenetic target for IGF1R axis-targeted therapeutic intervention.

Published
2022

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