Somatic rearrangements causing oncogenic ectodomain deletions of FGFR1 in squamous cell lung cancer

Abstract

The discovery of frequent 8p11-p12 amplifications in squamous cell lung cancer (SQLC) has fueled hopes that FGFR1, located inside this amplicon, might be a therapeutic target. In a clinical trial, only 11% of patients with 8p11 amplification (detected by FISH) responded to FGFR kinase inhibitor treatment. To understand the mechanism of FGFR1 dependency, we performed deep genomic characterization of 52 SQLCs with 8p11-p12 amplification, including 10 tumors obtained from patients who had been treated with FGFR inhibitors. We discovered somatically altered variants of FGFR1 with deletion of exons 1–8 that resulted from intragenic tail-to-tail rearrangements. These ectodomain-deficient FGFR1 variants (ΔEC-FGFR1) were expressed in the affected tumors and were tumorigenic in both in vitro and in vivo models of lung cancer. Mechanistically, breakage-fusion-bridges were the source of 8p11-p12 amplification, resulting from frequent head-to-head and tail-to-tail rearrangements. Generally, tail-to-tail rearrangements within or in close proximity upstream of FGFR1 were associated with FGFR1 dependency. Thus, the genomic events shaping the architecture of the 8p11-p12 amplicon provide a mechanistic explanation for the emergence of FGFR1-driven SQLC. Specifically, we believe that FGFR1 ectodomain–deficient and FGFR1 -centered amplifications caused by tail-to-tail rearrangements are a novel somatic genomic event that might be predictive of therapeutically relevant FGFR1 dependency.

Oncogene alterations in non-small cell lung cancer with FGFR1 amplification—novel approach to stratify patients who benefit from FGFR inhibitors

“…Recently, Malchers et al demonstrated that there’s a correlation between the oncogenic ectodomain deletion of FGFR1 caused by somatic rearrangements with tumor dependency on FGFR1 and sensitivity to FGFR inhibitors in SQCLC ( 23 ). By performing deep genomic sequencing of SQCLC samples with FGFR1 amplification, including patient samples treated with FGFR inhibitors, they identified two types of tail-to-tail rearrangements that happen within or close to the FGFR1 gene ( Figure 1 ).…”

“…The study by Malchers et al ( 23 ) suggests that the identification of tail-to-tail rearrangements within or close to the FGFR1 gene could be a potential new approach to select patients for FGFR inhibitor treatment. However, FGFR1 amplified SQCLC is still heterogenous.…”

“…A series of studies by the authors illustrates the complexity of SQCLC ( 13 , 23 , 25 ), probably due to tobacco smoking. It is hoped that continued research efforts will eventually build a targeted strategy for this difficult population.…”

High-resolution genomic configuration of FGFR rearrangements dictates the therapeutic vulnerability of squamous cell lung cancers

“…Squamous cell lung cancers (SQCLC) have significant cellular heterogeneity and few therapeutic targets. In the paper by Malchers et al , 8p11-p12 amplifications involving FGFR1 , frequently altered in SQCLC, have been examined by high-resolution deep-sequencing ( 1 ). The amplification of 8p11-p12 arises from breakage-fusion-bridges (BFB) and its genomic impact can vary with respect to genomic architecture of FGFR1 .…”

“…To dissect the heterogeneity in terms of molecular mechanisms of FGFR1 amplification and their impact on the efficacy to FGFR inhibitors, Malchers et al performed deep sequencing (hybrid capture-based sequencing) on 8p11-p12 amplifications across primary SQCLCs, cancer cell lines and patient-derived xenografts ( 1 ). Out of ten primary cases with FGFR1 amplification detected by traditional methods such as fluorescence in situ hybridization (FISH), only four responded to FGFR inhibitors confirming that FGFR1 amplification alone does not serve as predictive markers for FGFR inhibitors.…”