CRISPR-Mediated Kinome Editing Prioritizes a Synergistic Combination Therapy for FGFR1-Amplified Lung Cancer
| Autor: | Shun-Qing Liang, Haibin Deng, Ren-Wang Peng, Gregor J. Kocher, Sabina Berezowska, Qinghua Zhou, Zhang Yang, Rémy Bruggmann, Sean Hall, Yanyun Gao, Duo Xu, Thomas M. Marti, Ralph A. Schmid, Haitang Yang |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cancer Research animal structures Aged Animals Apoptosis Benzamides/pharmacology CRISPR-Cas Systems Cell Cycle Cell Cycle Proteins/antagonists & inhibitors Cell Cycle Proteins/genetics Cell Proliferation Combined Modality Therapy Gene Amplification Gene Expression Regulation Neoplastic Humans Lung Neoplasms/genetics Lung Neoplasms/metabolism Lung Neoplasms/pathology Lung Neoplasms/therapy Male Mice Piperazines/pharmacology Protein Kinase Inhibitors/pharmacology Protein Serine-Threonine Kinases/antagonists & inhibitors Protein Serine-Threonine Kinases/genetics Proto-Oncogene Proteins/antagonists & inhibitors Proto-Oncogene Proteins/genetics Pyrazoles/pharmacology Receptor Fibroblast Growth Factor Type 1/antagonists & inhibitors Receptor Fibroblast Growth Factor Type 1/genetics Tumor Cells Cultured Xenograft Model Antitumor Assays Cas9 DNA damage business.industry Drug resistance medicine.disease PLK1 3. Good health 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Oncology 030220 oncology & carcinogenesis embryonic structures Cancer cell Cancer research medicine CRISPR Kinome biological phenomena cell phenomena and immunity Lung cancer business |
| Zdroj: | Cancer research, vol. 81, no. 11, pp. 3121-3133 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-20-2276 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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