Synergistic effects of FGFR1 and PLK1 inhibitors target a metabolic liability in KRAS-mutant cancer.

Yang, Zhang; Liang, Shun-Qing; Saliakoura, Maria; Yang, Haitang; Vassella, Eric; Konstantinidou, Georgia; Tschan, Mario; Hegedüs, Balazs; Zhao, Liang; Gao, Yanyun; Xu, Duo; Deng, Haibin; Marti, Thomas M; Kocher, Gregor J; Wang, Wenxiang; Schmid, Ralph A; Peng, Ren-Wang (2021). Synergistic effects of FGFR1 and PLK1 inhibitors target a metabolic liability in KRAS-mutant cancer. EMBO molecular medicine, 13(9), e13193. EMBO Press 10.15252/emmm.202013193

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KRAS oncoprotein is commonly mutated in human cancer, but effective therapies specifically targeting KRAS-driven tumors remain elusive. Here, we show that combined treatment with fibroblast growth factor receptor 1 (FGFR1) and polo-like kinase 1 (PLK1) inhibitors evoke synergistic cytotoxicity in KRAS-mutant tumor models in vitro and in vivo. Pharmacological and genetic suppression of FGFR1 and PLK1 synergizes to enhance anti-proliferative effects and cell death in KRAS-mutant lung and pancreatic but not colon nor KRAS wild-type cancer cells. Mechanistically, co-targeting FGFR1 and PLK1 upregulates reactive oxygen species (ROS), leading to oxidative stress-activated c-Jun N-terminal kinase (JNK)/p38 pathway and E2F1-induced apoptosis. We further delineate that autophagy protects from PLK1/FGFR1 inhibitor cytotoxicity and that antagonizing the compensation mechanism by clinically approved chloroquine fully realizes the therapeutic potential of PLK1 and FGFR1 targeting therapy, producing potent and durable responses in KRAS-mutant patient-derived xenografts and a genetically engineered mouse model of Kras-induced lung adenocarcinoma. These results suggest a previously unappreciated role for FGFR1 and PLK1 in the surveillance of metabolic stress and demonstrate a synergistic drug combination for treating KRAS-mutant cancer.

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 > Pre-clinic Human Medicine > Institute of Pharmacology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Forschungsbereich Mu50 > Forschungsgruppe Thoraxchirurgie
04 Faculty of Medicine > Service Sector > Institute of Pathology
04 Faculty of Medicine > Service Sector > Institute of Pathology > Tumour Pathology

UniBE Contributor:

Yang, Zhang; Saliakoura, Maria; Yang, Haitang; Konstantinidou, Georgia; Tschan, Mario; Zhao, Liang; Gao, Yanyun; Xu, Duo; Deng, Haibin; Marti, Thomas; Kocher, Gregor; Schmid, Ralph and Peng, Ren-Wang

Subjects:

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

ISSN:

1757-4684

Publisher:

EMBO Press

Language:

English

Submitter:

Celine Joray

Date Deposited:

19 Oct 2021 17:36

Last Modified:

20 Oct 2021 01:34

Publisher DOI:

10.15252/emmm.202013193

PubMed ID:

34369083

Uncontrolled Keywords:

KRAS-mutant cancer autophagy fibroblast growth factor receptor 1 polo-like kinase 1 synthetic lethal vulnerability

BORIS DOI:

10.48350/160191

URI:

https://boris.unibe.ch/id/eprint/160191

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