Citation

BibTex format

@article{Chrysostomou:2021:10.1126/scitranslmed.aba4627,
author = {Chrysostomou, S and Roy, R and Prischi, F and Thamlikitkul, L and Chapman, KL and Mufti, U and Peach, R and Ding, L and Hancock, D and Moore, C and Molina-Arcas, M and Mauri, F and Pinato, DJ and Abrahams, JM and Ottaviani, S and Castellano, L and Giamas, G and Pascoe, J and Moonamale, D and Pirrie, S and Gaunt, C and Billingham, L and Steven, NM and Cullen, M and Hrouda, D and Winkler, M and Post, J and Cohen, P and Salpeter, SJ and Bar, V and Zundelevich, A and Golan, S and Leibovici, D and Lara, R and Klug, DR and Yaliraki, SN and Barahona, M and Wang, Y and Downward, J and Skehel, JM and Ali, MMU and Seckl, MJ and Pardo, OE},
doi = {10.1126/scitranslmed.aba4627},
journal = {Science translational medicine},
title = {Repurposed floxacins targeting RSK4 prevent chemoresistance and metastasis in lung and bladder cancer.},
url = {http://dx.doi.org/10.1126/scitranslmed.aba4627},
volume = {13},
year = {2021}
}

RIS format (EndNote, RefMan)

TY  - JOUR
AB - Lung and bladder cancers are mostly incurable because of the early development of drug resistance and metastatic dissemination. Hence, improved therapies that tackle these two processes are urgently needed to improve clinical outcome. We have identified RSK4 as a promoter of drug resistance and metastasis in lung and bladder cancer cells. Silencing this kinase, through either RNA interference or CRISPR, sensitized tumor cells to chemotherapy and hindered metastasis in vitro and in vivo in a tail vein injection model. Drug screening revealed several floxacin antibiotics as potent RSK4 activation inhibitors, and trovafloxacin reproduced all effects of RSK4 silencing in vitro and in/ex vivo using lung cancer xenograft and genetically engineered mouse models and bladder tumor explants. Through x-ray structure determination and Markov transient and Deuterium exchange analyses, we identified the allosteric binding site and revealed how this compound blocks RSK4 kinase activation through binding to an allosteric site and mimicking a kinase autoinhibitory mechanism involving the RSK4's hydrophobic motif. Last, we show that patients undergoing chemotherapy and adhering to prophylactic levofloxacin in the large placebo-controlled randomized phase 3 SIGNIFICANT trial had significantly increased (<i>P</i> = 0.048) long-term overall survival times. Hence, we suggest that RSK4 inhibition may represent an effective therapeutic strategy for treating lung and bladder cancer.
AU - Chrysostomou,S
AU - Roy,R
AU - Prischi,F
AU - Thamlikitkul,L
AU - Chapman,KL
AU - Mufti,U
AU - Peach,R
AU - Ding,L
AU - Hancock,D
AU - Moore,C
AU - Molina-Arcas,M
AU - Mauri,F
AU - Pinato,DJ
AU - Abrahams,JM
AU - Ottaviani,S
AU - Castellano,L
AU - Giamas,G
AU - Pascoe,J
AU - Moonamale,D
AU - Pirrie,S
AU - Gaunt,C
AU - Billingham,L
AU - Steven,NM
AU - Cullen,M
AU - Hrouda,D
AU - Winkler,M
AU - Post,J
AU - Cohen,P
AU - Salpeter,SJ
AU - Bar,V
AU - Zundelevich,A
AU - Golan,S
AU - Leibovici,D
AU - Lara,R
AU - Klug,DR
AU - Yaliraki,SN
AU - Barahona,M
AU - Wang,Y
AU - Downward,J
AU - Skehel,JM
AU - Ali,MMU
AU - Seckl,MJ
AU - Pardo,OE
DO - 10.1126/scitranslmed.aba4627
PY - 2021///
SN - 1946-6234
TI - Repurposed floxacins targeting RSK4 prevent chemoresistance and metastasis in lung and bladder cancer.
T2 - Science translational medicine
UR - http://dx.doi.org/10.1126/scitranslmed.aba4627
UR - http://hdl.handle.net/10044/1/90380
VL - 13
ER -