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

Zhang Yang,Balazs Hegedüs,Wenxiang Wang,Haibin Deng,Eric Vassella,Thomas M Marti,Ren‐Wang Peng,Shun‐Qing Liang,Haitang Yang,Ralph A Schmid,Liang Zhao,Duo Xu,Mario Tschan,Georgia Konstantinidou,Yanyun Gao,Maria Saliakoura,Gregor J Kocher

doi:10.15252/emmm.202013193

Abstract

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.

Highlights

KRAS oncoprotein is commonly mutated in human cancer, but effective therapies targeting KRAS-driven tumors remain elusive
We demonstrate that KRAS-mutant lung and pancreatic cancers are highly sensitive to concomitant inhibition of fibroblast growth factor receptor 1 (FGFR1) and polo-like kinase 1 (PLK1)
This sensitivity arises due to an underlying metabolic vulnerability such that upon FGFR1/PLK1 inhibition, oxidative stress surges due to cytotoxic reactive oxygen species (ROS) accumulation, leading to ROS-mediated hyperactivation of the Jun Nterminal kinase (JNK)/p38 signaling axis and E2F1-induced apoptosis

Summary

Introduction

KRAS oncoprotein is commonly mutated in human cancer, but effective therapies targeting KRAS-driven tumors remain elusive. 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 patientderived 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

Methods

Results

Conclusion