PhD project (Ruixuan Li): Identifying mechanisms of tyrosine kinase inhibitor resistance in breast cancer

FGF signalling is implicated in breast cancer susceptibility and progression, suggesting that this powerful developmental pathway is co-opted by breast cancer cells. FGFR signalling plays pivotal role not only in cancer progressions but also in cancer drug resistance through genetic alterations, activation of alternative signaling pathways, its interaction with the tumour microenvironmental, promoting EMT, and acquisition of stemness properties. Understanding the mechanisms underlying FGFR-mediated resistance can help guide the development of novel therapeutic approaches and combination strategies to improve treatment outcomes for cancer patients.



The aim of this study is to identify and understand the mechanisms involved in FGFR/TKI mediated resistance in breast cancer, to provide insights into the development of novel treatments and combination strategies to improve treatment outcomes for cancer patients.



Objectives:

To develop Breast Cancer Cell lines resistance to TKIs (e.g., FGFR TKI, AZD4547, that is used in clinical trials).

To further validate the clones by assessing whether downstream signalling (e.g., MAPK) upon recombinant ligand stimulation will be blocked by short time pre-treatment with the FGFR inhibitor PD173074 and AZD4547).

We will validate the functional differences (e.g., cell proliferation, migration, invasion, apoptosis, construct a 3D organotypic model) between the wild-type breast cancer cell lines and the drug resistance clones.

We will sequence FGFRs (1-4) to compare the sequences between wild type and drug resistance clones.

To perform transcriptomic or proteomics analysis between parental and drug resistant cell lines and validate the targets.

Breast cancer cells can hijack a natural system in the body called FGF signalling, which normally helps tissues grow and repair. When this system becomes overactive, it can make breast cancer more likely to develop, grow faster, and spread. It can also make cancer cells resistant to treatment. This resistance can happen for many reasons — such as changes in cancer cell genes, the activation of backup growth pathways, or support from nearby cells in the tumour environment.

The goal of this study is to understand how breast cancer cells become resistant to drugs that block FGFRs (fibroblast growth factor receptors), which are a key part of this signalling system. By understanding these resistance mechanisms, we hope to find better ways to treat patients, either with new drugs or combinations of existing ones.

To do this, we will:

Create breast cancer cell lines that become resistant to drugs known as FGFR inhibitors (including AZD4547, which is being tested in clinical trials).

Test how these resistant cells respond to growth signals and whether FGFR inhibitors can still block their activity.

Compare resistant and normal (non-resistant) cells for differences in growth, movement, invasion, and survival — including using 3D lab models that mimic real tissue.

Examine genetic changes in the FGFR family of receptors (FGFR1–4) between normal and resistant cells.

Use large-scale gene and protein analyses to identify key molecular changes responsible for drug resistance.

These findings will help reveal why some breast cancers stop responding to treatment and could guide the design of more effective therapies in the future.