CRISPR-Mediated Kinome Editing Prioritizes a Synergistic Combination Therapy for FGFR1-Amplified Lung Cancer.

Yang, Zhang; Liang, Shun-Qing; Yang, Haitang; Xu, Duo; Bruggmann, Rémy; Gao, Yanyun; Deng, Haibin; Berezowska, Sabina; Hall, Sean R R; Marti, Thomas M; Kocher, Gregor J; Zhou, Qinghua; Schmid, Ralph A; Peng, Ren-Wang (2021). CRISPR-Mediated Kinome Editing Prioritizes a Synergistic Combination Therapy for FGFR1-Amplified Lung Cancer. Cancer research, 81(11), pp. 3121-3133. American Association for Cancer Research AACR 10.1158/0008-5472.CAN-20-2276

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Oncogenic activation of the 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 antiproliferative 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. SIGNIFICANCE: The identification of PLK1 as a potent synthetic lethal target for FGFR-targeted therapy provides an innovative rationale for the treatment of lung and other FGFR1-amplified cancers.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Thoracic Surgery
04 Faculty of Medicine > Service Sector > Institute of Pathology > Clinical Pathology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Forschungsbereich Mu50 > Forschungsgruppe Thoraxchirurgie
04 Faculty of Medicine > Service Sector > Institute of Pathology

UniBE Contributor:

Yang, Zhang; Yang, Haitang; Xu, Duo; Bruggmann, Rémy; Gao, Yanyun; Deng, Haibin; Berezowska, Sabina Anna; Hall, Sean; Marti, Thomas; Kocher, Gregor; Schmid, Ralph and Peng, Ren-Wang

Subjects:

600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology

ISSN:

0008-5472

Publisher:

American Association for Cancer Research AACR

Language:

English

Submitter:

Thomas Michael Marti

Date Deposited:

06 Jul 2021 16:56

Last Modified:

06 Jul 2021 17:03

Publisher DOI:

10.1158/0008-5472.CAN-20-2276

PubMed ID:

33685992

BORIS DOI:

10.48350/157380

URI:

https://boris.unibe.ch/id/eprint/157380

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