48P - Development of resistance models to tyrosine kinase inhibitors (TKIs) in patient-derived xenograft models (PDXs) of lung adenocarcinoma with epiderm...

Date 17 April 2015
Event ELCC 2015
Session Poster lunch
Topics Basic Science
Lung and other Thoracic Tumours
Translational Research
Presenter Erin Stewart
Citation Annals of Oncology (2015) 26 (suppl_1): 10-14. 10.1093/annonc/mdv045
Authors E.L. Stewart1, S. Sakashita2, T. Wang2, N. Pham1, M. Li1, G. Liu3, M.S. Tsao4
  • 1Department Of Research, Princess Margaret Cancer Centre, M5G 1L7 - Toronto/CA
  • 2Pathology, Princess Margaret Cancer Centre, M5G 1L7 - Toronto/CA
  • 3Departments Of Research & Of Medical Oncology And Hematology, Princess Margaret Cancer Centre, M5G 2M9 - Toronto/CA
  • 4Departments Of Research & Of Pathology, Princess Margaret Cancer Centre, M5G 1L7 - Toronto/CA



Up to 80% of EGFR-mutant lung cancer patients respond to EGFR TKIs, but almost all will eventually develop resistance. Most studies on acquired resistance have used cell line models; however it has been suggested that cell lines may not fully recapitulate patients' disease. Our laboratory has successfully established 6 EGFR mutant PDX models from resected lung adenocarcinoma; we have developed resistance to TKIs in 2 of these models. Our goal is to use these models to further our understanding of mechanisms of resistance development to EGFR TKIs.


Tumour-bearing mice were treated until they reached humane endpoint for tolerance to TKI treatment, at which point the tumors were passaged into new mice to continue chronic TKI therapy. When tumours were too small for passaging, they were released from TKI therapy until the tumours reached a suitable volume for re-implantation. Mice continued to receive chronic exposure to the TKI after passaging. This method was repeated until resistance developed.


PDX model 137 has an exon 19 deletion EGFR mutation and was sensitive to erlotinib. PDX model 148 has an L858R EGFR mutation and MET amplification and was resistant to erlotinib but was sensitive to crizotinib. These PDXs were chronically treated with erlotinib and crizotinib, respectively. In both models, treatment for approximately 200 days resulted in 1 of 5 tumour-bearing mice developing resistance. For PDX model 137, passaging the resistant tumour led to a persistently resistant model, with all 10 replicates demonstrating resistance to erlotinib. For PDX model 148, passaging the resistant tumour led to 2 tumour-bearing mice exhibiting resistance, while the other 3 mice grew tumours that never grew above 300mm3. Molecular profiling is being conducted to gain insights into the mechanisms of resistance development.


PDXs derived from early-stage, surgically resected, EGFR-mutant NSCLC can mimic the clinical development of resistance to TKIs after chronic exposure. These models may be useful to identify novel mechanisms of resistance to TKI therapy.


G. Liu: Honoraria from AstraZeneca, Hoffmann-LaRoche, Novartis and Pfizer.

M.S. Tsao: Honoraria from AstraZeneca, Hoffmann-LaRoche, Boehringer-Ingelheim Canada, Novartis and Pfizer

All other authors have declared no conflicts of interest.