FGFR1 overexpression in non-small cell lung cancer is mediated by genetic and epigenetic mechanisms and is a determinant of FGFR1 inhibitor response

Olga Bogatyrova,Johanna S.M Mattsson,Edith M Ross,Michael P Sanderson,Max Backman,Johan Botling,Hans Brunnström,Pinja Kurppa,Linnéa La Fleur,Carina Strell,Claudia Wilm,Astrid Zimmermann,Christina Esdar,Patrick Micke

doi:10.1016/j.ejca.2021.04.005

Abstract

Amplification of fibroblast growth factor receptor 1 (FGFR1) in non-small cell lung cancer (NSCLC) has been considered as an actionable drug target. However, pan-FGFR tyrosine kinase inhibitors did not demonstrate convincing clinical efficacy in FGFR1-amplified NSCLC patients. This study aimed to characterise the molecular context of FGFR1 expression and to define biomarkers predictive of FGFR1 inhibitor response.In this study, 635 NSCLC samples were characterised for FGFR1 protein expression by immunohistochemistry and copy number gain (CNG) by in situ hybridisation (n = 298) or DNA microarray (n = 189). FGFR1 gene expression (n = 369) and immune cell profiles (n = 309) were also examined. Furthermore, gene expression, methylation and microRNA data from The Cancer Genome Atlas (TCGA) were compared. A panel of FGFR1-amplified NSCLC patient-derived xenograft (PDX) models were tested for response to the selective FGFR1 antagonist M6123.A minority of patients demonstrated FGFR1 CNG (10.5%) or increased FGFR1 mRNA (8.7%) and protein expression (4.4%). FGFR1 CNG correlated weakly with FGFR1 gene and protein expression. Tumours overexpressing FGFR1 protein were typically devoid of driver alterations (e.g. EGFR, KRAS) and showed reduced infiltration of T-lymphocytes and lower PD-L1 expression. Promoter methylation and microRNA were identified as regulators of FGFR1 expression in NSCLC and other cancers. Finally, NSCLC PDX models demonstrating FGFR1 amplification and FGFR1 protein overexpression were sensitive to M6123.The unique molecular and immune features of tumours with high FGFR1 expression provide a rationale to stratify patients in future clinical trials of FGFR1 pathway-targeting agents.

Highlights

The identification of activating mutations in the receptor tyrosine kinase (RTK) epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) patients and the subsequent approval of EGFR inhibitors, such as gefitinib and erlotinib, heralded a new era of targeted therapy in the treatment paradigm of NSCLC [1,2]
These findings suggest that mechanisms beyond gene amplification contribute to the overexpression of fibroblast growth factor receptor 1 (FGFR1) in a subset of NSCLC patients
FGFR1 overexpression was only weakly linked to FGFR1 amplification and could better be explained by promoter demethylation or downregulation of specific miRNAs

Summary

Introduction

The identification of activating mutations in the receptor tyrosine kinase (RTK) epidermal growth factor receptor (EGFR) in NSCLC patients and the subsequent approval of EGFR inhibitors, such as gefitinib and erlotinib, heralded a new era of targeted therapy in the treatment paradigm of NSCLC [1,2] This initial breakthrough was followed by the approval of other targeted therapies in molecularly defined NSCLC patients, such as those harbouring ALK or ROS1 fusions and more recently, the development of more effective second- and third-generation agents, which selectively target the mutant forms of oncogenic driver proteins like EGFR and ALK [3,4]. These successes have led to the more recent development of novel targeted agents against underserviced driver alterations, including those previously considered undruggable, such as the G12C mutated form of KRAS [13,14]

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