Somatic rearrangements causing oncogenic ectodomain deletions of FGFR1 in squamous cell lung cancer
Florian Malchers, … , Julie George, Roman K. Thomas
Florian Malchers, … , Julie George, Roman K. Thomas
Published August 22, 2023
Citation Information: J Clin Invest. 2023;133(21):e170217. https://doi.org/10.1172/JCI170217.
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Research Article Genetics Oncology

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.

Authors

Florian Malchers, Lucia Nogova, Martijn H.A. van Attekum, Lukas Maas, Johannes Brägelmann, Christoph Bartenhagen, Luc Girard, Graziella Bosco, Ilona Dahmen, Sebastian Michels, Clare E. Weeden, Andreas H. Scheel, Lydia Meder, Kristina Golfmann, Philipp Schuldt, Janna Siemanowski, Jan Rehker, Sabine Merkelbach-Bruse, Roopika Menon, Oliver Gautschi, Johannes M. Heuckmann, Elisabeth Brambilla, Marie-Liesse Asselin-Labat, Thorsten Persigehl, John D. Minna, Henning Walczak, Roland T. Ullrich, Matthias Fischer, Hans Christian Reinhardt, Jürgen Wolf, Reinhard Büttner, Martin Peifer, Julie George, Roman K. Thomas

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Figure 4

Rearrangements associated with FGFR inhibitor sensitivity.

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Rearrangements associated with FGFR inhibitor sensitivity. (A) GI50 of 1...
(A) GI50 of 118 cancer cell lines treated with BGJ398 or JQ.1, sorted according to the presence or absence of somatic FGFR gene family alterations (left) or the presence or absence of FGFR1 amplification (excluding other FGFR alterations, right). *P < 0.05. (B) Average GI50 values of 8 cell lines (>1 μM in red; <1 μM in blue) treated with the FGFR inhibitors BGJ398 or AZD4547. (C) Average tumor growth reduction of 8 PDX tumor models treated with 20 mg/kg BGJ398 or vehicle control (resistant red, tumor reduction <30 %; sensitive blue, tumor reduction >30 %). Asterisks indicate samples provided by Weeden et al. (13). (D) Average copy number of 6 cell lines resistant to (red) and 2 cell lines sensitive to (blue) FGFR inhibition (top panel) and 5 resistant (red) and 3 sensitive (blue) PDX tumor models (bottom panel). NSD3 and FGFR1 are highlighted (orange). Locations of genes (wedges) are indicated below (yellow, positive strand; blue, negative strand). Rearrangements in samples from responders are indicated. (E) Illustration of 3 possible rearrangements and their impact on copy number (see Supplemental Video 1 for a detailed explanation). (F) Average copy number of 25 8p-amplified primary SQLC specimens with unknown responsiveness to FGFR inhibition (whole-genome sequenced). Data are plotted together (gray, n = 25) or with (400 kb range, blue, n = 9) or without observed tail-to-tail rearrangements (>1 mb range, red, n = 16) before FGFR1. Magnification of the amplification peak is shown (right, blue group, n = 9). Only rearrangements observed within the ORF of NSD3 or FGFR1 are indicated (arrows). Corresponding rearrangements within the same sample are also indicated, if located within the same sample (black lines) and if detected within the magnified area (arrows: head-to-head in green, normal in black, and tail-to-tail in red).