In Vitro and In Vivo Activity of Lucitanib in FGFR1/2 Amplified or Mutated Cancer Models

Guffanti, Federica; Chilà, Rosaria; Bello, Ezia; Zucchetti, Massimo; Zangarini, Monique; Ceriani, Laura; Ferrari, Mariella; Lupi, Monica; Jacquet-Bescond, Anne; Burbridge, Mike F.; Pierrat, Marie-Jeanne; Damia, Giovanna

doi:10.1016/j.neo.2016.11.008

Cited by 29 publications

(23 citation statements)

References 40 publications

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“…Due to their implication in numerous cancer types, clinical trials are underway for a number of small-molecule inhibitors targeting FGFRs (20,21). However, resistance is a major problem with any targeted therapy using small-molecule inhibitors, with one common mechanism of resistance in kinases occurring via the gatekeeper mutation (22,23).…”

Section: Introductionmentioning

confidence: 99%

The FGFR1 V561M Gatekeeper Mutation Drives AZD4547 Resistance through STAT3 Activation and EMT

Ryan

Sohl

Luo

et al. 2019

Molecular Cancer Research

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FGFR1 has been implicated in numerous cancer types including squamous cell lung cancer, a subset of non-small cell lung cancer with a dismal 5-year survival rate. Smallmolecule inhibitors targeting FGFR1 are currently in clinical trials, with AZD4547 being one of the furthest along; however, the development of drug resistance is a major challenge for targeted therapies. A prevalent mechanism of drug resistance in kinases occurs through mutation of the gatekeeper residue, V561M in FGFR1; however, mechanisms underlying V561M resistance to AZD4547 are not fully understood. Here, the cellular consequences of the V561M gatekeeper mutation were characterized, and it was found that although AZD4547 maintains nanomolar affinity for V561M FGFR1, based on in vitro binding assays, cells expressing V561M demonstrate dramatic resistance to AZD4547 driven by increased STAT3 activation downstream of V561M FGFR1. The data reveal that the V561M mutation biases cells toward a more mesenchymal phenotype, including increased levels of proliferation, migration, invasion, and anchorage-independent growth, which was confirmed using CyTOF, a novel single-cell analysis tool. Using shRNA knockdown, loss of STAT3 restored sensitivity of cancer cells expressing V561M FGFR1 to AZD4547. Thus, the data demonstrate that combination therapies including FGFR and STAT3 may overcome V561M FGFR1-driven drug resistance in the clinic.Implications: The V561M FGFR1 gatekeeper mutation leads to devastating drug resistance through activation of STAT3 and the epithelial-mesenchymal transition; this study demonstrates that FGFR1 inhibitor sensitivity can be restored upon STAT3 knockdown.

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Section: Introductionmentioning

confidence: 99%

The FGFR1 V561M Gatekeeper Mutation Drives AZD4547 Resistance through STAT3 Activation and EMT

Ryan

Sohl

Luo

et al. 2019

Molecular Cancer Research

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“…The binding mode, interaction between molecule and active site, binding energy and docking score generated by the co-execution of LibDock and CDOCEER can facilitate us to screen the optimal docking posture. E-3810, also known as Lucitanib, is a novel small molecule drug that selectively binds RTK to the ATPbinding capsule of VEGFR1-3, PDGFRα/β, and FGFR1-3 receptor tyrosine kinases as competitive inhibitors, thereby impeding receptor dimerization and downstream signaling [31,32]. E-3810 was added with polar hydrogen and stored after energy optimization using the CHARMm force eld.…”

Section: Molecular Dockingmentioning

confidence: 99%

Ligand based 3D-QSAR pharmacophore, molecular docking and ADME to identify potential fibroblast growth factor receptor 1 inhibitors

Tang

Wang

et al. 2020

Preprint

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Background The FGF/FGFR system may affect tumor cells and stromal microenvironment through autocrine and paracrine stimulation, thereby significantly promoting oncogene transformation and tumor growth. Abnormal expression of FGFR1 in cells is considered to be the main cause of tumorigenesis and a potential target for the treatment of cancer.Methods The known inhibitors were collected to construct 3D-QSAR pharmacophore model, which was verified by cost analysis, test set validation and Fischer test. Virtual screening of zinc database based on pharmacophore was carried out. FGFR1 crystal complex was downloaded from the protein database to dock with the compound. Finally, the absorption, distribution, metabolism and excretion (ADME) characteristics and toxicity of a series of potential inhibitors were studied.Results It was found that the constructed pharmacophore had a good ability to predict the activity. 2763 compounds in the database could hit well and the predicted activity value was less than 1 µM. Through molecular docking, we found that six compounds can bind to protein stably and inhibit the activity of FGFR1 through hydrogen bond interaction. In ADME and toxicity studies, we have successfully screened out a compound with a new structure scaffold, and found that it has good oral bioavailability and non-toxic.Conclusions This study screened out a new potential drug for cancer treatment, which can be further studied to explore its better therapeutic effect.

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“…COX2 has been reported to counteract the efficacy of anti-angiogenic agents 164 . Lucitanib (a multi-target inhibitor of VEGFR1 to 3, PDGFRα/β, and FGFR1 to 3) has demonstrated activity in phase I/II clinical testing in patients with breast cancer 165 . Another novel method to overcome resistance to bevacizumab therapy is combining VEGF inhibitors with pericyte-targeted drugs (mostly inhibitors of Ang or PDGFRβ).…”

Section: Targeting Tumor Microenvironment To Overcome Therapeutic Resmentioning

confidence: 99%

The role of tumor microenvironment in resistance to anti-angiogenic therapy

Pradeep

et al. 2018

F1000Res

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Anti-angiogenic therapy has been demonstrated to increase progression-free survival in patients with many different solid cancers. Unfortunately, the benefit in overall survival is modest and the rapid emergence of drug resistance is a significant clinical problem. Over the last decade, several mechanisms have been identified to decipher the emergence of resistance. There is a multitude of changes within the tumor microenvironment (TME) in response to anti-angiogenic therapy that offers new therapeutic opportunities. In this review, we compile results from contemporary studies related to adaptive changes in the TME in the development of resistance to anti-angiogenic therapy. These include preclinical models of emerging resistance, dynamic changes in hypoxia signaling and stromal cells during treatment, and novel strategies to overcome resistance by targeting the TME.

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In Vitro and In Vivo Activity of Lucitanib in FGFR1/2 Amplified or Mutated Cancer Models

Cited by 29 publications

References 40 publications

The FGFR1 V561M Gatekeeper Mutation Drives AZD4547 Resistance through STAT3 Activation and EMT

The FGFR1 V561M Gatekeeper Mutation Drives AZD4547 Resistance through STAT3 Activation and EMT

Ligand based 3D-QSAR pharmacophore, molecular docking and ADME to identify potential fibroblast growth factor receptor 1 inhibitors

The role of tumor microenvironment in resistance to anti-angiogenic therapy

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