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

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机构： [1]Division of General Thoracic Surgery,Inselspital, Bern University Hospital, University of Bern, Switzerland [2]Department for BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern, Switzerland [3]Interfaculty Bioinformatics Unit and Swiss Institute of Bioinformatics, University of Bern, Bern, Switzerland [4]Institute of Pathology, University of Bern, Bern, Switzerland [5]Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China [6]University of Massachusetts Medical School, Worcester, MA 01605, USA

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关键词： Lung cancer FGFR1 amplification CRISPR screen PLK1 synergistic combination therapy

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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. Copyright ©2021, American Association for Cancer Research.

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出版当年[2021]版：

大类 | 1 区

医学

小类 | 1 区肿瘤学

最新[2023]版：

大类 | 1 区

医学

小类 | 2 区肿瘤学

第一作者：

第一作者机构： [1]Division of General Thoracic Surgery,Inselspital, Bern University Hospital, University of Bern, Switzerland [2]Department for BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern, Switzerland

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通讯机构： [1]Division of General Thoracic Surgery,Inselspital, Bern University Hospital, University of Bern, Switzerland [2]Department for BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern, Switzerland [*1]Division of General Thoracic Surgery, Department for BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern, Murtenstrasse 50, 3008 Bern, Switzerland

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

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