TARGETING FGFR1 IN METASTATIC BREAST CANCER

Reason: There are unpublished data in this thesis.

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TARGETING FGFR1 IN METASTATIC BREAST CANCER

thesis
posted on 30.01.2022, 18:27 authored by Hang LinHang Lin

Metastasis remains the major cause of breast cancer (BC)-related death as developing an effective therapeutic strategy for the treatment of metastatic breast cancer (MBC) is a major clinical challenge. Fibroblast growth factor receptor (FGFR) is an emerging target for MBC as its expression is amplified in metastases and FGFR1 can be upregulated in MBC cells through the process of epithelial-mesenchymal transition (EMT). Inactivation of FGFR by tyrosine kinase inhibitors (TKIs) has achieved great success in various types of cancer. However, FGFR TKI resistance has become a concern in improving MBC patients’ outcomes. Therefore, it is critical to develop advanced therapeutic interventions for improving patients’ survival. In this dissertation work, we investigated novel therapeutic avenues to target FGFR1 in MBC.

To date, a variety of FGFR TKIs have been evaluated in clinical trials or clinically approved for cancer treatment. However, the efficacies of FGFR TKIs in MBC remain unclear. Herein, we evaluated the efficacies of several experimental and clinically approved FGFR TKIs using 3D culture and in vivo model systems. Our results demonstrated that FGFR-targeted kinase inhibitors are completely effective at blocking ligand-induced cell growth but fail to eliminate dormant BC cells. Moreover, animals succumb to disease progression while on therapy. Therefore, we explored broader approaches to inhibit FGFR1 expression in addition to blockade of its kinase activity.

Proteolysis targeting chimeras (PROTACs), heterobifunctional molecules inducing degradation of protein of interest via proteasome machinery, have emerged as a powerful tool for targeted cancer therapies. Together with our collaborators, we developed an array of FGFR PROTACs. Here, we showed that FGFR PROTACs inhibited metastatic and drug-resistant BC cell growth. Furthermore, our results identified potential FGFR PROTACs which induced FGFR1 degradation and blocked FGFR1 downstream signaling. Using 3D culture, FGFR PROTACs are shown to target MBC aggressiveness. Hence, our data suggested that PROTAC-mediated FGFR1 degradation is a promising strategy for MBC therapies.

In addition to the aforementioned approaches, G-quadruplex (G4) is revealed highlighting new possibilities for anticancer therapies. The Examination of the FGFR1 proximal promoter indicated sequences forming potential for G-quadruplex (G4) secondary structures. We found that G4 stabilizing agents are able to block constitutive and EMT-induced expression of FGFR1. Additionally, G4 stabilizers could effectively block ectopic FGFR1 expression derived from CMV promoter driven constructs. Importantly, use of the clinical G4-targeting compound CX-5461 suppresses FGFR1 promoter activity, targets FGFR1 expression, and inhibited FGFR1 downstream signaling, resulting in eradication of dormant breast cancer cells. Finally, in vivo application of CX-5461 reduced FGFR1 expression, blocked pulmonary tumor formation, and prolonged animal survival. Overall, our findings indicated that targeting FGFR1 expression through G4 stabilization may be a potential therapeutic strategy for MBC.

FGFR1 has attracted great attention as a therapeutic target in a variety of tumors. In this dissertation work, we have identified the potential FGFR kinase-independent function which may contribute to TKI resistance. Moreover, we have revealed novel therapeutic options to overcome FGFR TKI resistance and achieve significant antitumor responses in MBC. In the future, our innovative therapeutic strategies can serve as an influential tool to investigate the FGFR1 regulation and kinase-independent function during metastasis.

History

Degree Type

Doctor of Philosophy

Department

Medicinal Chemistry and Molecular Pharmacology

Campus location

West Lafayette

Advisor/Supervisor/Committee Chair

Michael K. Wendt

Additional Committee Member 2

Zhong-Yin Zhang

Additional Committee Member 3

Emily C. Dykhuizen

Additional Committee Member 4

Luis Solorio