Advertisement
Commentary
Open Access | 
10.1172/JCI174171
Genomic insights into the mechanisms of FGFR1 dependency in squamous cell lung cancer
Netta Mäkinen1,2 and Matthew Meyerson1,2,3
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
2Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
3Departments of Genetics and Medicine, Harvard Medical School, Boston, Massachusetts, USA.
Address correspondence to: Matthew Meyerson, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA. Phone: 617.632.4768; Email: matthew_meyerson@dfci.harvard.edu.
Find articles by Mäkinen, N. in: JCI | PubMed | Google Scholar
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
2Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
3Departments of Genetics and Medicine, Harvard Medical School, Boston, Massachusetts, USA.
Address correspondence to: Matthew Meyerson, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA. Phone: 617.632.4768; Email: matthew_meyerson@dfci.harvard.edu.
Find articles by
Meyerson, M.
in:
JCI
|
PubMed
|
Google Scholar
|
Published November 1, 2023 - More info
J Clin Invest. 2023;133(21):e174171. https://doi.org/10.1172/JCI174171.
© 2023 Mäkinen, et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Related article:
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
-
Potential mechanisms of FGFR1 dependency
In this issue of the JCI, Malchers and authors performed a detailed genomic characterization of FGFR1-amplified LSCC samples to further study the mechanisms of FGFR1 dependency (24). These efforts expand on their previous finding of marked heterogeneity among the 8p11-12 amplification events in LSCC due to the presence of multiple centers of amplification in the chromosomal region (25). FGFR1 was observed to locate in the epicenter of the amplicon in only 28% of all 8p11-12–amplified cases. In their current article, Malchers et al. describe two types of genomic alterations that are associated with FGFR1 dependency and, thus, sensitivity to FGFR inhibition: tail-to-tail rearrangements within FGFR1 and in close proximity to FGFR1 (24) (Figure 1).
Figure 1Two types of FGFR1 rearrangements are associated with sensitivity to FGFR inhibition in LSCC. Only a subset of patients with LSCC characterized by amplification of the 8p11-12 region, which houses the putative FGFR1 oncogene, respond to FGFR inhibition. Malchers et al. showed that LSCC tumors with intragenic tail-to-tail rearrangements within FGFR1 and in close proximity to FGFR1 were associated with FGFR1 dependency (24). Screening patients for these rearrangement events may identify those more likely to benefit from treatment with FGFR inhibitors.
Tail-to-tail rearrangements within FGFR1 were identified in 8% (4 of 52) of the FGFR1-amplified LSCC samples, leading to various deletions in the extracellular region of the protein. Half of the rearrangements were present in patients with a partial response to FGFR inhibition (infigratinib or pazopanib) and the other half in untreated patients. Interestingly, FGFR1 ectodomain truncations resulted in retained protein expression and catalytic function of FGFR1 in the affected tumors. Additionally, the truncated FGFR1 variants were shown to be oncogenic and sensitive to FGFR inhibition (infigratinib and AZD4547) both in vitro and in vivo.
Tail-to-tail rearrangements in close proximity to FGFR1 were observed in 27% (14 of 52) of FGFR1-amplified LSCC samples. Four alterations were present in either lung cancer cell lines or patient-derived xenograft models sensitive to FGFR inhibitors (infigratinib or AZD4547), one in a patient with a partial response to FGFR inhibition, and nine in untreated patients. These rearrangements led to an FGFR1-centered amplification pattern in the samples and frequently co-occurred with disruptive rearrangements of NSD3 (64%; 9 of 14), a neighboring gene of FGFR1.
In summary, Malchers and colleagues identified recurrent tail-to-tail rearrangements within and in close proximity to FGFR1 in 8p11-12–amplified LSCC samples sensitive to FGFR inhibition. They propose that these specific rearrangements could be predictive of therapeutically relevant FGFR1 dependency. Not all the study findings by Malchers and co-authors, however, fit neatly under this assumption. Two FGFR1-amplified LSCC samples that responded to FGFR inhibitors (22%; 2 of 9) did not harbor FGFR1 ectodomain–deficient variants or FGFR1-centered amplifications, although one of the samples did display a disruptive NSD3 rearrangement (24). Also, tail-to-tail rearrangements in close proximity to FGFR1 were observed in three samples unresponsive to FGFR inhibition (24).
Failure of FGFR1 amplification to reliably predict a response to FGFR inhibition in LSCC has raised the possibility that genes other than FGFR1 in the 8p11-12–amplified region could be driving or contributing to tumorigenesis. A recent study on NSD3 reproduced previous studies nominating this gene as an oncogenic driver in LSCC and suggested that NSD3 dependency renders LSCC therapeutically vulnerable to bromodomain inhibition (26). Malchers and authors observed disruptive NSD3 rearrangements only in FGFR inhibitor–sensitive samples (56%; 5 of 9) and proposed that sensitivity to FGFR inhibition in these samples was primarily driven by FGFR1, whereas the role of NSD3 in these tumors was unlikely functional (24). They also showed that bromodomain inhibition had no effect on the viability of Ba/F3 cells expressing ectodomain-deficient FGFR1 (24).
Copyright © 2024 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)