Poster Presentation 28th Lorne Cancer Conference 2016

FGFR1 inhibition in patient-derived xenograft models of lung squamous cell carcinoma (#111)

Clare Weeden 1 , Aliaksei Holik 1 , Richard J Young 2 , Prue Russel 3 , Gavin Wright 3 , Matthew Ritchie 4 , Ben Solomon 5 6 , Marie-Liesse Asselin-Labat 1
  1. ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
  2. Molecular Therapeutics and Biomarkers, Peter MacCallum Cancer Centre, Melbourne, VIctoria, -Australia
  3. St Vincent's Hospital, Melbourne, VIC, Australia
  4. Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  5. Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
  6. Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne , VIC, Australia

Identification of genetic alterations in Fibroblast Growth Factor Receptors (FGFRs) in lung squamous cell carcinoma (SqCC) has generated immense interest in the use of FGFR inhibitors in the clinic. However, results from clinical trials have shown that some, but not all FGFR1-amplified tumors are responsive to FGFR-targeted therapy suggesting that other biomarkers will be required to better stratify patients and predict response to therapy.

To better evaluate tumor response to novel therapies, we have established a bank of Patient-Derived Xenograft (PDX) models of lung SqCC and demonstrated that PDXs recapitulate the histological phenotype of the patient’s tumour. Furthermore, RNA sequencing and SNP array showed that the range of genetic alterations present in human tumors was conserved in the resulting mouse xenograft tumours.

We used these SqCC PDXs to evaluate the activity of FGFR inhibitors in vivo. Tumors with FGFR amplification showed response to the FGFR inhibitor BGJ398, while efficacy was profoundly increased when BGJ398 was combined with another targeted therapy. Significantly we also identified a PDX that responded to FGFR inhibition although the tumor did not present FGFR1 gene amplification. We found that this PDX overexpressed FGFR1 mRNA by in situ hybridization, suggesting overexpression of FGFR1 mRNA may be a better biomarker predictive of response to FGFR inhibitors. Analysis of FGFR1 mRNA expression in a non-small cell lung cancer tissue micro-array showed that 34% of tumors express high levels of FGFR1 mRNA whereas only 12.5% had FGFR1 amplification. FGFR1 amplified tumors were exclusively detected in SqCC whereas FGFR1 mRNA overexpression was observed across different histological subtypes, including adenocarcinoma.

Our results demonstrate that PDXs permit the evaluation of combination therapies based on the molecular characteristics of a patient tumour, providing relevant preclinical models to improve personalized medicine. Furthermore, we show that FGFR1 mRNA expression may be a better biomarker to predict response to FGFR inhibition that may benefit lung cancer patients with squamous cell carcinoma as well as adenocarcinoma.