Petra Martin1, Erin Stewart2, Nhu-An Pham3, Celine Mascaux1, Devang Panchal3, Ming Li3, Lucia Kim3, Shingo Sakashita4, Dennis Wang3, Jenna Sykes3, Thomas Friess5, Frances A Shepherd1, Geoffrey Liu1, Ming-Sound Tsao6. 1. Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada. 2. Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. 3. Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. 4. Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. 5. Department of Pharmacology, Roche Diagnostics GmbH, Mannheim, Germany. 6. Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Electronic address: Ming.Tsao@uhn.ca.
Abstract
BACKGROUND: The epidermal growth factor receptor (EGFR) kinase domain T790M (amino acid substitution at position 790 in EGFR from threonine [T] to methionine [M]) mutation in non-small-cell lung cancer (NSCLC) results in resistance to EGFR tyrosine kinase inhibitors (TKIs). We used a patient-derived tumor xenograft (PDX) model containing an EGFR exon 19 deletion/T790M mutation to assess response to the EGFR-directed antibody cetuximab. Changes in the EGFR signaling pathway and ligand expression after treatment were investigated. METHODS: PDX were randomized into control and treatment arms. Pharmacodynamic studies were performed at 2 and 24 hours and at 4 days after a single administration of cetuximab, erlotinib, or dacomitinib. Changes in the EGFR signaling pathway were assessed using Western blot analysis, and baseline mRNA expression of EGFR ligands using microarray analysis. Relative changes after treatment were assessed using quantitative polymerase chain reaction. RESULTS: The xenograft showed a dramatic response to cetuximab. A complete reduction of total EGFR and phosphorylated EGFR occurred after cetuximab treatment. The PDX had increased baseline levels of heparin-binding epidermal growth factor-like growth factor (HB-EGF) compared with other PDX models with or without EGFR mutations. Amphiregulin was significantly reduced 2 hours after treatment with cetuximab. Compared with control mice, cetuximab- and EGFR-TKI-treated mice had significantly reduced HB-EGF gene expression at 2 hours, however, by day 4 the level of HB-EGF expression was higher. The effect of cetuximab compared with EGFR TKI on HB-EGF gene expression levels differed significantly at 2 and 24 hours but not at 4 days. CONCLUSION: We showed a dramatic tumor response with cetuximab in an exon 19 deletion/T790M EGFR mutant lung adenocarcinoma PDX model, which suggests a role for the autocrine feedback loop in the mutant EGFR signaling pathway. Further investigation using cetuximab in NSCLC with T790M mutation is warranted.
BACKGROUND: The epidermal growth factor receptor (EGFR) kinase domain T790M (amino acid substitution at position 790 in EGFR from threonine [T] to methionine [M]) mutation in non-small-cell lung cancer (NSCLC) results in resistance to EGFR tyrosine kinase inhibitors (TKIs). We used a patient-derived tumor xenograft (PDX) model containing an EGFR exon 19 deletion/T790M mutation to assess response to the EGFR-directed antibody cetuximab. Changes in the EGFR signaling pathway and ligand expression after treatment were investigated. METHODS: PDX were randomized into control and treatment arms. Pharmacodynamic studies were performed at 2 and 24 hours and at 4 days after a single administration of cetuximab, erlotinib, or dacomitinib. Changes in the EGFR signaling pathway were assessed using Western blot analysis, and baseline mRNA expression of EGFR ligands using microarray analysis. Relative changes after treatment were assessed using quantitative polymerase chain reaction. RESULTS: The xenograft showed a dramatic response to cetuximab. A complete reduction of total EGFR and phosphorylated EGFR occurred after cetuximab treatment. The PDX had increased baseline levels of heparin-binding epidermal growth factor-like growth factor (HB-EGF) compared with other PDX models with or without EGFR mutations. Amphiregulin was significantly reduced 2 hours after treatment with cetuximab. Compared with control mice, cetuximab- and EGFR-TKI-treated mice had significantly reduced HB-EGF gene expression at 2 hours, however, by day 4 the level of HB-EGF expression was higher. The effect of cetuximab compared with EGFR TKI on HB-EGF gene expression levels differed significantly at 2 and 24 hours but not at 4 days. CONCLUSION: We showed a dramatic tumor response with cetuximab in an exon 19 deletion/T790MEGFR mutant lung adenocarcinoma PDX model, which suggests a role for the autocrine feedback loop in the mutant EGFR signaling pathway. Further investigation using cetuximab in NSCLC with T790M mutation is warranted.
Authors: Carolin Sellmann; Achim Doerner; Christine Knuehl; Nicolas Rasche; Vanita Sood; Simon Krah; Laura Rhiel; Annika Messemer; John Wesolowski; Mark Schuette; Stefan Becker; Lars Toleikis; Harald Kolmar; Bjoern Hock Journal: J Biol Chem Date: 2016-09-30 Impact factor: 5.157
Authors: Yushi Li; Joyce W Y Chan; Rainbow W H Lau; Winnie W Y Cheung; Alissa Michelle Wong; Aikha M Wong; Nathalie Wong; Calvin Sze Hang Ng Journal: Front Surg Date: 2021-12-09