CRISPR-mediated kinome editing prioritizes a synergistic combination therapy for FGFR1-amplified lung cancer.

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State: Public
Version: Author's accepted manuscript
License: Not specified
Serval ID
serval:BIB_6D844130F3DD
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
CRISPR-mediated kinome editing prioritizes a synergistic combination therapy for FGFR1-amplified lung cancer.
Journal
Cancer research
Author(s)
Yang Z., Liang S.Q., Yang H., Xu D., Bruggmann R., Gao Y., Deng H., Berezowska S., Hall SRR, Marti T.M., Kocher G.J., Zhou Q., Schmid R.A., Peng R.W.
ISSN
1538-7445 (Electronic)
ISSN-L
0008-5472
Publication state
Published
Issued date
08/03/2021
Peer-reviewed
Oui
Language
english
Notes
Publication types: Journal Article
Publication Status: aheadofprint
Abstract
Oncogenic activation of the fibroblast growth factor receptor (FGFR) pathway is frequent in lung and other cancers. However, due to drug resistance, pharmacological blockage of aberrant FGFR signaling has provided little clinical benefit in patients with FGFR-amplified tumors. The determining factors for the limited efficacy of FGFR-targeted therapy remain incompletely understood. In this study, we performed kinome-wide CRISPR/Cas9 loss-of-function screens in FGFR1-amplified lung cancer cells treated with an FGFR inhibitor. These screens identified PLK1 as a potent synthetic lethal target that mediates a resistance mechanism by overriding DNA damage and cell cycle arrest upon FGFR1 inhibition. Genetic and pharmacological antagonism of PLK1 in combination with FGFR inhibitor therapy synergized to enhance anti-proliferative effects and drove cancer cell death in vitro and in vivo through activation of the γH2AX-CHK-E2F1 axis. These findings suggest a previously unappreciated role for PLK1 in modulating FGFR1 inhibitor sensitivity and demonstrate a synergistic drug combination for treating FGFR1-amplified lung cancer.
Pubmed
Create date
15/03/2021 15:02
Last modification date
24/04/2021 7:10
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