Cell-Autonomous and Non–Cell-Autonomous Mechanisms of Transformation by Amplified <i>FGFR1</i> in Lung Cancer

Malchers, Florian; Dietlein, Felix; Schöttle, Jakob; Lü, Xin; Nogová, Lucia; Albus, Kerstin; Fernández-Cuesta, Lynnette; Heuckmann, Johannes M.; Gautschi, Oliver; Diebold, Joachim; Plenker, Dennis; Gardizi, Masyar; Scheffler, Matthias; Bos, Marc; Seidel, Danila; Leenders, Frauke; Richters, André; Peifer, Martin; Florin, Alexandra; Mainkar, Prathama S.; Karre, Nagaraju; Chandrasekhar, S.; George, Julie; Silling, Steffi; Rauh, Daniel; Zander, Thomas; Ullrich, Roland T.; Reinhardt, Hans Christian; Ringeisen, François; Büttner, Reinhard; Heukamp, Lukas C.; Wolf, Jürgen; Thomas, Roman K.

doi:10.1158/2159-8290.cd-13-0323

Cited by 90 publications

(94 citation statements)

References 39 publications

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“…S1). As expected, FGFR inhibitor treatment led to decreased ERK phosphorylation in parental cells (2)(3)(4)(6)(7)(8). Of interest, all resistant cells exhibited sustained ERK phosphorylation under 1 mmol/L of FGFR inhibitor treatment (Fig.…”

Section: A Subclonal Population Of Fgfr Inhibitor-resistant Cellssupporting

confidence: 75%

“…5). We and others have discovered FGFR1 amplifications in SQLC that were associated with sensitivity to FGFR inhibition in preclinical models (6)(7)(8).…”

Section: Introductionmentioning

confidence: 90%

“…S5A). We performed comprehensive tumor genome characterization using NEO comprehensive genomic sequencing technology on a tumor biopsy taken before initiation of anti-FGFR therapy (5,8,(18)(19)(20)23). We detected a TP53 (p.R248L) mutation and a CDKN2A (p.G23fs) frame-shift mutation.…”

Section: Met Activation In a Patient Relapsing After Initial Responsementioning

confidence: 99%

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Mechanisms of Primary Drug Resistance in FGFR1-Amplified Lung Cancer

Malchers

Ercanoglu

Schütte

et al. 2017

Clinical Cancer Research

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Purpose: The 8p12-p11 locus is frequently amplified in squamous cell lung cancer (SQLC); the receptor tyrosine kinase fibroblast growth factor receptor 1 (FGFR1) being one of the most prominent targets of this amplification. Thus, small molecules inhibiting FGFRs have been employed to treat FGFR1-amplified SQLC. However, only about 11% of such FGFR1-amplified tumors respond to single-agent FGFR inhibition and several tumors exhibited insufficient tumor shrinkage, compatible with the existence of drug-resistant tumor cells.Experimental Design: To investigate possible mechanisms of resistance to FGFR inhibition, we studied the lung cancer cell lines DMS114 and H1581. Both cell lines are highly sensitive to three different FGFR inhibitors, but exhibit sustained residual cellular viability under treatment, indicating a subpopulation of existing drug-resistant cells. We isolated these subpopulations by treating the cells with constant high doses of FGFR inhibitors.Results: The FGFR inhibitor-resistant cells were cross-resistant and characterized by sustained MAPK pathway activation. In drug-resistant H1581 cells, we identified NRAS amplification and DUSP6 deletion, leading to MAPK pathway reactivation. Furthermore, we detected subclonal NRAS amplifications in 3 of 20 (15%) primary human FGFR1-amplified SQLC specimens. In contrast, drug-resistant DMS114 cells exhibited transcriptional upregulation of MET that drove MAPK pathway reactivation. As a consequence, we demonstrate that rational combination therapies resensitize resistant cells to treatment with FGFR inhibitors.Conclusions: We provide evidence for the existence of diverse mechanisms of primary drug resistance in FGFR1-amplified lung cancer and provide a rational strategy to improve FGFR inhibitor therapies by combination treatment.

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Section: A Subclonal Population Of Fgfr Inhibitor-resistant Cellssupporting

confidence: 75%

“…5). We and others have discovered FGFR1 amplifications in SQLC that were associated with sensitivity to FGFR inhibition in preclinical models (6)(7)(8).…”

Section: Introductionmentioning

confidence: 90%

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Mechanisms of Primary Drug Resistance in FGFR1-Amplified Lung Cancer

Malchers

Ercanoglu

Schütte

et al. 2017

Clinical Cancer Research

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“…KRAS and RTK alterations occurred in a near mutually exclusive pattern, but PIK3CA, PTEN alterations, and FGFR alterations overlapped in patients with lung squamous carcinoma (6) and endometrial cancer (8). In squamous cell lung cancer, MYC was coexpressed in about 40% of FGFR1-amplified tumors, and this coexpression was associated with sensitivity to FGFR inhibitors (39). These results suggest that in addition to the presence of FGFR abnormalities, the expression level of FGFRs or the status of other molecules should be investigated to select patients suitable for treatment with E7090.…”

Section: Discussionmentioning

confidence: 99%

E7090, a Novel Selective Inhibitor of Fibroblast Growth Factor Receptors, Displays Potent Antitumor Activity and Prolongs Survival in Preclinical Models

Miyano

Yamamoto

Kodama

et al. 2016

Molecular Cancer Therapeutics

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The FGFR signaling pathway has a crucial role in proliferation, survival, and migration of cancer cells, tumor angiogenesis, and drug resistance. FGFR genetic abnormalities, such as gene fusion, mutation, and amplification, have been implicated in several types of cancer. Therefore, FGFRs are considered potential targets for cancer therapy. E7090 is an orally available and selective inhibitor of the tyrosine kinase activities of FGFR1, -2, and -3. In kinetic analyses of the interaction between E7090 and FGFR1 tyrosine kinase, E7090 associated more rapidly with FGFR1 than did the type II FGFR1 inhibitor ponatinib, and E7090 dissociated more slowly from FGFR1, with a relatively longer residence time, than did the type I FGFR1 inhibitor AZD4547, suggesting that its kinetics are more similar to the type V inhibitors, such as lenvatinib. E7090 showed selective antiproliferative activity against cancer cell lines harboring FGFR genetic abnormalities and decreased tumor size in a mouse xenograft model using cell lines with dysregulated FGFR. Furthermore, E7090 administration significantly prolonged the survival of mice with metastasized tumors in the lung. Our results suggest that E7090 is a promising candidate as a therapeutic agent for the treatment of tumors harboring FGFR genetic abnormalities. It is currently being investigated in a phase I clinical trial. Mol Cancer Ther; 15(11); 2630-9. Ó2016 AACR.

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“…These diverse ligand-receptor combinations mediate multiple developmental programs during embryogenesis, as well as adult tissue repair and maintenance. Elevated FGFR1 expression and upregulation of FGFR/ FGF signaling apparently lead to cell transformation and lung carcinogenesis (20)(21)(22)(23)(24), and negatively affects the survival of patients (14,25). It has been demonstrated, using cell cultures and xenografted mouse models, that SCC carrying FGFR1 gene amplifications responds effectively to therapy that blocks FGFR1 activity (14,26), revealing the first high-frequency targetable oncogene specific for smoking-associated lung cancer (27).…”

Section: Introductionmentioning

confidence: 99%

High-Affinity Internalizing Human scFv-Fc Antibody for Targeting FGFR1-Overexpressing Lung Cancer

Sokołowska-Wędzina

Chodaczek

Chudzian

et al. 2017

Molecular Cancer Research

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Targeted delivery of anticancer drugs using antibodies specific for tumor-associated antigens represents one of the most important approaches in current immuno-oncology research. Fibroblast growth factor receptor 1 (FGFR1) has been demonstrated to be a high-frequency targetable oncogene specific for smokingassociated lung cancers, present in over 20% of lung squamous cell carcinoma cases. This report describes the generation of a potent, fully human antibody fragment in scFv-Fc format efficiently targeting FGFR1. Antibody phage display was used to select high-affinity scFv antibody fragments against the extracellular domain of FGFR1(IIIc). Enzyme immunoassay (ELISA) and surface plasmon resonance (SPR) analysis were used for antibody screening and characterization. The best binder (named D2) was cloned to diabody and Fc fusion formats. All D2 antibodies demonstrated high affinity for FGFR1 with dissociation constants of 18 nmol/L (scFvD2), 0.82 nmol/L (scFvD2 diabody), and 0.59 nmol/L (scFvD2-Fc). scFvD2 was found to be exquisitely selective for FGFR1 versus other FGFR family members and bound FGFR1 even in the presence of its natural ligand FGF2, as shown by competitive analysis. Confocal microscopy revealed that scFvD2-Fc was specifically and rapidly internalized by a panel of cell lines overexpressing FGFR1. Finally, it was demonstrated that scFvD2-Fc mediated specific delivery of a cytotoxic payload into lung cancer cells harboring oncogenic FGFR1 gene amplifications.Implications: This study reports a highly specific internalizing antibody fragment that can serve as a therapeutic targeting agent for efficient delivery of cytotoxic drugs into FGFR1-positive lung cancer cells. Mol Cancer Res; 15(8); 1040-50. Ó2017 AACR.

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Cell-Autonomous and Non–Cell-Autonomous Mechanisms of Transformation by Amplified FGFR1 in Lung Cancer

Cited by 90 publications

References 39 publications

Mechanisms of Primary Drug Resistance in FGFR1-Amplified Lung Cancer

Mechanisms of Primary Drug Resistance in FGFR1-Amplified Lung Cancer

E7090, a Novel Selective Inhibitor of Fibroblast Growth Factor Receptors, Displays Potent Antitumor Activity and Prolongs Survival in Preclinical Models

High-Affinity Internalizing Human scFv-Fc Antibody for Targeting FGFR1-Overexpressing Lung Cancer

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