BibTex format
@inproceedings{Chrysostomou:2019:10.1158/1538-7445.AM2019-1775,
author = {Chrysostomou, S and Roy, R and Prischi, F and Chapman, K and Mufti, U and Mauri, F and Bellezza, G and Abrahams, J and Ottaviani, S and Castellano, L and Giamas, G and Hrouda, D and Winkler, M and Klug, D and Yaliraki, S and Barahona, M and Wang, Y and Ali, M and Seckl, M and Pardo, O},
doi = {10.1158/1538-7445.AM2019-1775},
pages = {1--2},
publisher = {American Association for Cancer Research},
title = {Abstract 1775: Targeting RSK4 prevents both chemoresistance and metastasis in lung cancer},
url = {http://dx.doi.org/10.1158/1538-7445.AM2019-1775},
year = {2019}
}
RIS format (EndNote, RefMan)
TY - CPAPER
AB - Lung cancer is the commonest cause of cancer death worldwide with a five-year survival rate of less than five percent for metastatic tumors. Non-small cell lung cancer (NSCLC) accounts for 80% of lung cancer cases of which adenocarcinoma prevails. Patients almost invariably develop metastatic drug-resistant disease and this is responsible for our failure to provide curative therapy. Hence, a better understanding of the mechanisms underlying these biological processes is urgently required to improve clinical outcome.The 90-kDa ribosomal S6 kinases (RSKs) are downstream effectors of the RAS/MAPK cascade. RSKs are highly conserved serine/threonine protein kinases implicated in diverse cellular processes, including cell survival, proliferation, migration and invasion. Four isoforms exist in humans (RSK1-4) and are uniquely characterized by the presence of two non-identical N- and C-terminal kinase domains. RSK isoforms are 73-80% identical at protein level and this has been thought to suggest overlapping functions.However, through functional genomic kinome screens, we show that RSK4, contrary to RSK1, promotes both drug resistance and metastasis in lung cancer. This kinase is overexpressed in the majority (57%) of NSCLC biopsies and this correlates with poor overall survival in lung adenocarcinoma patients. Genetic silencing of RSK4 sensitizes lung cancer cells to chemotherapy and prevents their migration and invasiveness in vitro and in vivo. RSK4 downregulation decreases the anti-apoptotic proteins Bcl2 and cIAP1/2 which correlates with increased apoptotic signalling, whilst it also induces mesenchymal-epithelial transition (MET) through inhibition of NFκB activity. A small-molecule inhibitor screen identified several floxacins, including trovafloxacin, as potent allosteric inhibitors of RSK4 activation. Trovafloxacin reproduced all biological and molecular effects of RSK4 silencing in vitro and in vivo, and is predicted to bind a novel allosteric site revealed
AU - Chrysostomou,S
AU - Roy,R
AU - Prischi,F
AU - Chapman,K
AU - Mufti,U
AU - Mauri,F
AU - Bellezza,G
AU - Abrahams,J
AU - Ottaviani,S
AU - Castellano,L
AU - Giamas,G
AU - Hrouda,D
AU - Winkler,M
AU - Klug,D
AU - Yaliraki,S
AU - Barahona,M
AU - Wang,Y
AU - Ali,M
AU - Seckl,M
AU - Pardo,O
DO - 10.1158/1538-7445.AM2019-1775
EP - 2
PB - American Association for Cancer Research
PY - 2019///
SN - 0008-5472
SP - 1
TI - Abstract 1775: Targeting RSK4 prevents both chemoresistance and metastasis in lung cancer
UR - http://dx.doi.org/10.1158/1538-7445.AM2019-1775
UR - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000488129904297&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR - https://cancerres.aacrjournals.org/content/79/13_Supplement/1775
UR - http://hdl.handle.net/10044/1/92879
ER -
