Covalent Targeting of Fibroblast Growth Factor Receptor Inhibits Metastatic Breast Cancer

Wells S Brown; Li Tan; Andrew Smith; Nathanael S Gray; Michael K Wendt

doi:10.1158/1535-7163.MCT-16-0136

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Covalent Targeting of Fibroblast Growth Factor Receptor Inhibits Metastatic Breast Cancer

Journal article

Open access

Peer reviewed

Covalent Targeting of Fibroblast Growth Factor Receptor Inhibits Metastatic Breast Cancer

Wells S Brown, Li Tan, Andrew Smith, Nathanael S Gray and Michael K Wendt

Molecular cancer therapeutics, Vol.15(9), pp.2096-2106

09/01/2016

DOI: 10.1158/1535-7163.MCT-16-0136

PMCID: PMC5010989

PMID: 27371729

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https://doi.org/10.1158/1535-7163.MCT-16-0136View

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Abstract

Therapeutic targeting of late-stage breast cancer is limited by an inadequate understanding of how tumor cell signaling evolves during metastatic progression and by the currently available small molecule inhibitors capable of targeting these processes. Herein, we demonstrate that both β3 integrin and fibroblast growth factor receptor-1 (FGFR1) are part of an epithelial-mesenchymal transition (EMT) program that is required to facilitate metastatic outgrowth in response to fibroblast growth factor-2 (FGF2). Mechanistically, β3 integrin physically disrupts an interaction between FGFR1 and E-cadherin, leading to a dramatic redistribution of FGFR1 subcellular localization, enhanced FGF2 signaling and increased three-dimensional (3D) outgrowth of metastatic breast cancer cells. This ability of β3 integrin to drive FGFR signaling requires the enzymatic activity of focal adhesion kinase (FAK). Consistent with these mechanistic data, we demonstrate that FGFR, β3 integrin, and FAK constitute a molecular signature capable of predicting decreased survival of patients with the basal-like subtype of breast cancer. Importantly, covalent targeting of a conserved cysteine in the P-loop of FGFR1-4 with our newly developed small molecule, FIIN-4, more effectively blocks 3D metastatic outgrowth as compared with currently available FGFR inhibitors. In vivo application of FIIN-4 potently inhibited the growth of metastatic, patient-derived breast cancer xenografts and murine-derived metastases growing within the pulmonary microenvironment. Overall, the current studies demonstrate that FGFR1 works in concert with other EMT effector molecules to drive aberrant downstream signaling, and that these events can be effectively targeted using our novel therapeutics for the treatment of the most aggressive forms of breast cancer. Mol Cancer Ther; 15(9); 2096-106. ©2016 AACR.

Animals

Antineoplastic Agents - pharmacology

Breast Neoplasms - drug therapy

Breast Neoplasms - metabolism

Breast Neoplasms - mortality

Breast Neoplasms - pathology

Cell Line, Tumor

Disease Models, Animal

Drug Resistance, Neoplasm

Epithelial-Mesenchymal Transition - genetics

Female

Fibroblast Growth Factor 2 - metabolism

Focal Adhesion Protein-Tyrosine Kinases - metabolism

Humans

Integrin beta3 - metabolism

Mice

Neoplasm Metastasis

Protein Kinase Inhibitors - pharmacology

Receptor, Fibroblast Growth Factor, Type 1 - metabolism

Receptors, Fibroblast Growth Factor - antagonists & inhibitors

Receptors, Fibroblast Growth Factor - genetics

Receptors, Fibroblast Growth Factor - metabolism

Signal Transduction - drug effects

Triple Negative Breast Neoplasms - genetics

Triple Negative Breast Neoplasms - metabolism

Triple Negative Breast Neoplasms - pathology

Twist-Related Protein 1 - genetics

Twist-Related Protein 1 - metabolism

Xenograft Model Antitumor Assays

Details

Title: Subtitle: Covalent Targeting of Fibroblast Growth Factor Receptor Inhibits Metastatic Breast Cancer
Creators: Wells S Brown - Purdue University West Lafayette
Li Tan - Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
Andrew Smith - Purdue University West Lafayette
Nathanael S Gray - Dana-Farber Cancer Institute
Michael K Wendt - Purdue University West Lafayette
Resource Type: Journal article
Publication Details: Molecular cancer therapeutics, Vol.15(9), pp.2096-2106
DOI: 10.1158/1535-7163.MCT-16-0136
PMID: 27371729
PMCID: PMC5010989
ISSN: 1535-7163
eISSN: 1538-8514
Grant note: R00 CA166140 / NCI NIH HHS P50 CA090578 / NCI NIH HHS P30 CA023168 / NCI NIH HHS
Language: English
Date published: 09/01/2016
Academic Unit: Internal Medicine
Record Identifier: 9984459624302771

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