China
Africa
Explore chapters and articles related to this topic
Hepatic Cancer
Published in Dongyou Liu, Tumors and Cancers, 2017
Important somatic mutations and deregulated signaling pathways concern TERT promoter (telomere stability), TP53 (cell cycle control), CTNNB1 and AXIN1 (Wnt/β-catenin signaling), ARID1A and ARID2 (chromatin remodeling), NFE2L2 and KEAP1 (oxidative stress), RPS6KA3 (RAS/MAPK signaling), JAK1 (JAK/STAT pathway), and PI3K/AKT (PI3K-AKT-mTOR pathway) [2,3].
Identifying requirements for RSK2 specific inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Eric B. Wright, Shinji Fukuda, Mingzong Li, Yu Li, George A. O’Doherty, Deborah A. Lannigan
The relative amount of inhibitor bound to RSK2 was determined using the LanthaScreen Eu Kinase Binding Assay for RPS6KA3 (Invitrogen). Kinase, Eu anti-His antibody, inhibitor or vehicle, and Kinase Tracer 236 (tracer) in kinase buffer were incubated as described in Figure 1(D), with final assay concentrations of 5 nM kinase, 2 nM antibody, inhibitor or vehicle (0.95% DMSO), and 15 nM tracer in Proxiplate white 384-well plates (Perkin Elmer) with 15 μL total assay volume per well. For RSK1 and RSK2 NTKD, 2 nM Eu Streptavidin and 2 nM Biotin anti-His antibody (Invitrogen) and for RSK3/4, 2 nM Eu anti-GST antibody (Invitrogen) were used in place of the Eu anti-His antibody. Time resolved fluorescence was measured with a Synergy Neo 2 Multi Mode Plate Reader and Gen5 software (Biotek) with excitation fluorescence at 330 ± 80 nm and emission measured at 620 ± 10 nm (background fluorescence from Eu antibody) and at 665 ± 8 nm (emission from fluorescence resonance energy transfer, FRET, from tracer) with 100 μs delay and 200 μs collection time. For each time point, emission ratio (EMR) was calculated as emission at 665 nm divided by emission at 620 nm. The corresponding average EMR of wells without inhibitor or kinase was subtracted, and background-subtracted EMR was normalised to average vehicle control. Normalised EMR was calculated in MATLAB (Mathworks).
The dawn of targeted therapies for triple negative breast cancer (TNBC): a snapshot of investigational drugs in phase I and II trials
Published in Expert Opinion on Investigational Drugs, 2020
My-my Huynh, Mary Rose Pambid, Aarthi Jayanthan, Andrew Dorr, Gerrit Los, Sandra E. Dunn
Recently, there has been considerable interest in targeting p90 ribosomal S6 kinase 2 (RSK2, RPS6KA3), downstream of MEK and ERK. RSK2 has emerged from siRNA functional screens and the use of RSK specific inhibitors in preclinical studies of TNBC cells in vitro and xenografts in vivo, show that RSK is an ideal target for TNBC [56,57]. RSK2 is a convergence point of the PDK-1 and MAPK pathways; more specifically it is phosphorylated by both ERK and PDK-1, transporting RSK2 from the cytoplasm into the nucleus to activate its targets. One of RSK2’s most important targets is Y-box binding protein-1 (YB-1), a transcription factor that is involved in cell survival, proliferation, and drug resistance [58,59]. RSK2 is highly expressed in TNBC and is a poor prognostic factor for patients [59]. A number of RSK inhibitors (RSKi) have been in pre-clinical development, but due to poor pharmacokinetics, they have not made it to the clinic [60]. Recently, however, the first-in-class oral RSKi PMD-026 began first-in-human studies and is currently in a phase I/Ib trial, in tandem development with a RSK2 companion diagnostic (NCT04115306) [61]. Given that RSK is downstream of MEK/ERK and PDK-1 in their respective signaling pathways, RSK has a limited set of substrates, therefore potentially fewer side effects are anticipated compared to inhibitors targeting kinases further upstream, such as MEK and ERK [56]. In particular, the inhibition of RSK, unlike MEK, does not cause activation of AKT, and therefore confers a distinct advantage because it does not activate this resistance pathway [62].
Comprehensive analysis of the RSK gene family in acute myeloid leukemia determines a prognostic signature for the prediction of clinical prognosis and treatment responses
Published in Hematology, 2023
Shasha Wu, Jiao Jin, Jing Huang, Guifang Chen, Yan Chen
The RSK family comprises four human isoforms (RPS6KA1, RPS6KA2, RPS6KA3, and RPS6KA6) and two structurally related homologues (RSP6KA4 and RSP6KA5). RSK gene family members share a high degree of sequence homology (75–80% amino-acid identity) and are uniquely characterized by the presence of two distinct functional kinase domains [12,13].