Abstract A142: In vivo response and molecular characterization of a Caucasian NSCLC squamous cell carcinoma PDX sensitive to FGFR inhibitor.
Authors: McKenzie Andrew J. , Cranston Aaron N. , Papadopoulou Nektaria , Jiang Simon , Wrigley Jane , Yin Yinfei , Li Henry , Page Martin , Kumari Rajendra 
Published: August 2014

Introduction: Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer cases, carries a poor prognosis and remains an area of high unmet need. Despite recent advances in treating defined subsets of NSCLC adenocarcinomas with targeted agents such as erlotinib and crizotinib few advances have been made in the treatment of squamous cell carcinoma (SCC), which accounts for 25% of all NSCLC. Although the incidence of fibroblast growth factor receptor (FGFR) mutations in SCC is modest, amplification of FGFR is well documented and there are several first generation FGFR tyrosine kinase inhibitors (TKI) currently in clinical trials. It is therefore essential to develop relevant in vivo patient-derived xenograft (PDX) 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: LU6429 is a novel Caucasian NSCLC SCC PDX model which is maintained subcutaneously in vivo admixed with a human stromal cell component. Cohorts of mice were dosed with AZD4547, which is an FGFR TKI undergoing evaluation in the clinic, alone or in combination with chemotherapy (CTx; parallel or serial dosing regimens). The extent of inhibition was measured over several in vivo passages and following cryopreservation/resuscitation. CTx and FGFR TKI resistant models of LU6429 were generated in vivo through repeated dosing and the resulting models characterized for their treatment response. Tumor material was characterized for 50 key oncogenes and mutations by Ion Torrent sequencing, for FGFR1-3 expression and genomic amplification by quantitative PCR and FGFR1-2 by FISH analysis. Immunohistochemistry (IHC) was used to confirm NSCLC subtype and EMT status.

Results: LU6429 PDX tumours (SCC confirmed by IHC) exhibited reproducible sensitivity to AZD4547 alone (P&lt;0.001) which was maintained both in continuous serial passage and following cryopreservation (at -196°C). FGFR expression, amplification and mutational analysis were assessed in naïve tumour material, following 10 weeks of continuous dosing and following outgrowth from CTx treatment and correlated with treatment response.

Conclusions: LU6429 is a novel patient-derived NSCLC SCC xenograft model with reproducible FGFR TKI sensitivity, which is directly relevant to the clinical setting. This model could be invaluable in assessing novel agents targeting the FGFR pathway and in the development of new combination strategies which may prevent or overcome resistance.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A142.

Citation Format: Andrew J. McKenzie, Aaron N. Cranston, Nektaria Papadopoulou, Simon Jiang, Jane Wrigley, Yinfei Yin, Henry Li, Martin Page, Rajendra Kumari. In vivo response and molecular characterization of a Caucasian NSCLC squamous cell carcinoma PDX sensitive to FGFR inhibitor. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A142.