Cancers of the respiratory system, including lung squamous cell carcinoma (SCC) and
nasopharyngeal carcinoma (NPC), are aggressive malignancies with low survival rates.
This is largely due to late detection and a lack of targeted therapeutic agents. Identifying
the molecular drivers of cancer permits for a better understanding of tumour progression
and an opportunity for the development of targeted treatment strategies.
Sequencing studies have revealed the presence of a genetic fusion between
fibroblast growth factor receptor 3 (FGFR3) and transforming acidic coiled-coil 3
(TACC3) in subset of lung SCC and NPCs. To interrogate the role of FGFR3-TACC3 in
oncogenic transformation of the respiratory epithelium we have utilised a combination in
vitro and sophisticated in vivo approaches.
We have demonstrated that expression of the FGFR3-TACC3 fusion protein
increased the proliferation potential of human lung SCC cells. Furthermore, FGFR3-
TACC3 expressing lung SCC cells were sensitive to an FGFR inhibitor compound,
revealing the efficacy of clinically available targeted therapies in the treatment of FGFR3-
TACC3-driven cancers.
Notably, conditional activation of FGFR3-TACC3 in vivo promoted hyperplastic
transformation of respiratory epithelial cells lining the nasal cavity. Combined loss of
tumour suppressor gene, p53, accelerated these effects, indicating that FGFR3-TACC3
and p53 loss co-operate in tumourgenesis. Taken together, this model provides an
effective tool to examine FGFR3-TACC3-driven malignant transformation, facilitating a
comprehensive understanding on how FGFR3-TACC3-expressing cancers can be
effectively targeted in the clinic.