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In Vivo Function of an EGFR Ligand in Lung Cancer
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A2683 - In Vivo Function of an EGFR Ligand in Lung Cancer
Author Block: Y. Maeda1, K. Tomoshige1, M. Guo2, I. Fink-Baldauf1; 1Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH, United States, 2Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.
Rationale: EGFR ligands (e.g., EGF and TGFalpha) have been shown to promote tumorigenesis using lung cancer cell lines in vitro. However, transgenic mouse models indicate that TGFalpha (an EGFR ligand) initiates the formation of tumors in liver, breast and pancreas but not in lung, suggesting that an EGFR ligand promotes lung tumors but does not initiate them in vivo. In this study, we aim to determine in vivo the function of an EGFR ligand (TGFalpha) using transgenic mouse models.
Methods: By crossing transgenic mice inducing autochthonous lung tumors driven by either EGFR.L858R or Kras.G12D with transgenic mice inducing TGFalpha in lung epithelium, we assessed whether TGFalpha influenced lung tumorigenesis driven by EGFR.L858R or Kras.G12D in vivo. Functional studies using H1975 TKI-resistant EGFR-mutant lung cancer cell line were performed to validate the in vivo data.
Results: TGFalpha promoted lung tumorigenesis driven by EGFR.L858R but not by KrasG12D in vivo. Notably, AGR2 (disulphide isomerase) and TP63 (airway basal cell and lung squamous cell markers) were significantly induced in EGFR.L858R-lung tumors promoted by TGFalpha. An in vitro loss of function study using H1975 EGFR-mutant lung cancer cell line indicated that AGR2 is required for lung tumorigenesis promoted by TGFalpha in H1975 cells.
Conclusions: Although TGFalpha (an EGFR ligand) has been shown to promote Kras-mutant pancreatic cancer in vivo, our study indicates that TGFalpha does not promote Kras-mutant lung tumors but rather promotes EGFR-mutant lung tumors, suggesting tissue-specific tumorigenic mechanisms regulated by TGFalpha. Since TGFalpha also promotes TKI-resistant H1975 lung tumor cells in vitro, targeting EGFR ligands, including TGFalpha, using antibody (e.g., CIMAvax-EGF) may provide a therapeutic benefit for TKI-resistant EGFR-mutant lung cancer.
Author Block: Y. Maeda1, K. Tomoshige1, M. Guo2, I. Fink-Baldauf1; 1Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH, United States, 2Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.
Rationale: EGFR ligands (e.g., EGF and TGFalpha) have been shown to promote tumorigenesis using lung cancer cell lines in vitro. However, transgenic mouse models indicate that TGFalpha (an EGFR ligand) initiates the formation of tumors in liver, breast and pancreas but not in lung, suggesting that an EGFR ligand promotes lung tumors but does not initiate them in vivo. In this study, we aim to determine in vivo the function of an EGFR ligand (TGFalpha) using transgenic mouse models.
Methods: By crossing transgenic mice inducing autochthonous lung tumors driven by either EGFR.L858R or Kras.G12D with transgenic mice inducing TGFalpha in lung epithelium, we assessed whether TGFalpha influenced lung tumorigenesis driven by EGFR.L858R or Kras.G12D in vivo. Functional studies using H1975 TKI-resistant EGFR-mutant lung cancer cell line were performed to validate the in vivo data.
Results: TGFalpha promoted lung tumorigenesis driven by EGFR.L858R but not by KrasG12D in vivo. Notably, AGR2 (disulphide isomerase) and TP63 (airway basal cell and lung squamous cell markers) were significantly induced in EGFR.L858R-lung tumors promoted by TGFalpha. An in vitro loss of function study using H1975 EGFR-mutant lung cancer cell line indicated that AGR2 is required for lung tumorigenesis promoted by TGFalpha in H1975 cells.
Conclusions: Although TGFalpha (an EGFR ligand) has been shown to promote Kras-mutant pancreatic cancer in vivo, our study indicates that TGFalpha does not promote Kras-mutant lung tumors but rather promotes EGFR-mutant lung tumors, suggesting tissue-specific tumorigenic mechanisms regulated by TGFalpha. Since TGFalpha also promotes TKI-resistant H1975 lung tumor cells in vitro, targeting EGFR ligands, including TGFalpha, using antibody (e.g., CIMAvax-EGF) may provide a therapeutic benefit for TKI-resistant EGFR-mutant lung cancer.
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