Abstract 769: In vivo response and molecular characterization of a Caucasian NSCLC squamous cell carcinoma PDX sensitive to FGFR inhibitors
Authors: McKenzie Andrew , Papadopoulou Nektaria , Yin Yinfei , Jiang Simon , Wrigley Jane , Cai Jie , Page Martin , Li Henry , Kumari Rajendra 
Published: August 2015

BACKGROUND:

The fibroblast growth factor receptor (FGFR) family are reported to be involved in key cellular processes such as proliferation, differentiation, migration & survival with the deregulation of signalling through genetic modification or amplification being observed in cancer. FGFR1 has been reported to be amplified in squamous cell non-small cell lung cancer (NSCLC) as well as other indications (e.g. breast) and there are several FGFR inhibitors currently in clinical trial. It is therefore essential to develop relevant in vivo models for the development and characterisation of new FGFR agents and/or combination strategies which may prolong benefit and delay the emergence of resistance.

METHODS:

Patient derived xenograft (PDX) models were maintained subcutaneously in vivo in serial passage and their growth monitored by calliper measurements three times weekly; mice were recruited to treatment groups when the mean tumour volume was approximately 200mm3. Response to treatment was evaluated by tumour growth inhibition in response to FGFR inhibitors such as AZD4547 and chemotherapy. Resistance to both chemotherapy (Paclitaxel/Carboplatin) and AZD4547 in the squamous cell carcinoma (SCC) PDX model, LU6429, was generated in vivo through repeated dosing and the resulting models characterised for their treatment response. Molecular characterisation was carried out by RNA sequencing.

RESULTS: A number of novel PDX models have been developed which harbour FGFR amplification and mutations including LU6429, a Caucasian NSCLC SCC PDX model which has modest FGFR1 and FGFR2 amplification and responds to FGFR inhibitors. LU6429 PDX tumours (SCC confirmed by IHC) exhibited reproducible sensitivity to AZD4547 (p&lt;0.001) which was maintained in continuous serial passage and following cryogenic storage. FGFR expression and mutational analysis was assessed in naïve tumours, tumours following continuous AZD4547 treatment and in the acquired chemo-resistance setting. Other models show differential response to FGFR inhibitors.

CONCLUSIONS: Pre-clinical models such as LU6429, a novel patient-derived NSCLC SCC xenograft model with moderate FGFR amplification which showed significant sensitivity to the FGFR inhibitor AZD4547, are invaluable in assessing novel agents targeting the FGFR pathway and in the development of new combination strategies which may prevent or overcome resistance.

Citation Format: Andrew McKenzie, Nektaria Papadopoulou, Yinfei Yin, Simon Jiang, Jane Wrigley, Jie Cai, Martin Page, Henry Li, Rajendra Kumari. In vivo response and molecular characterization of a Caucasian NSCLC squamous cell carcinoma PDX sensitive to FGFR inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 769. doi:10.1158/1538-7445.AM2015-769