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T. Fukazawa

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    P1.02 - Biology/Pathology (ID 614)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P1.02-014 - TGFalpha Promotes Growth of Lung Tumors Carrying EGFR Mutation but not KRAS Mutation in Transgenic Mouse Models in Vivo (ID 8029)

      09:30 - 16:00  |  Author(s): T. Fukazawa

      • Abstract

      TGFalpha, one of the EGFR ligands (EGF, TGFA, AREG, EREG, HBEGF, BTC and EPGN), is known to be associated with poor survival in human lung adenocarcinoma (Tateishi et al., Cancer Res 1990). However, it remains unknown whether TGFalpha promotes EGFR-mutant lung adenocarcinoma and/or KRAS-mutant lung adenocarcinoma in vivo.

      In order to understand the role of TGFalpha in lung cancer in vivo, we developed transgenic mice that conditionally induce mutant EGFR (Politi et al., Gene Dev 2006) or mutant KRAS (Fisher et al., Gene Dev 2001) along with TGFalpha (Hardie et al., Am J Physiol Lung Cell Mol Physiol 2004) in lung epithelium and analyzed the survival and histology of the mice. Based on the mouse study, we also investigated the association of TGFalpha with EGFR mutation or KRAS mutation in human lung cancer using TCGA databases (TCGA, Nature 2012; 2014), lung cancer cell lines and lung cancer specimens.

      TGFalpha enhanced the growth of EGFR-mutant lung tumors but not that of KRAS-mutant lung tumors in the transgenic mice. The growth of EGFR-mutant lung tumors enhanced by TGFalpha was accompanied by the expression of two key tumor-promoting regulators p63 (a marker for airway basal cells and lung squamous cell carcinoma cells) and AGR2 (disulphide isomerase). TGFalpha was associated with poor survival in EGFR-mutant lung adenocarcinoma but not in EGFR wild-type adenocarcinoma (e.g., KRAS-mutant lung adenocarcinoma) in human lung cancer. Although osimertinib and brigatinib have been shown to be clinically and preclinically effective for the treatment of gefitinib and erlotinib-resistant EGFR-mutant lung adenocarcinoma, including EGFR.T790M or EGFR.C797S (Goss et al., Lancet Oncol 2016; Mok et al., N Engl J Med 2017; Uchidori et al., Nat Commun 2017), the history of moleculary-targeted therapy for EGFR-mutant lung adenocarcinoma indicates that lung tumor clones resistant to osimertinib and brigatinib would likely emerge. Our results suggest that blocking EGFR ligands (e.g., TGFalpha and/or EGF) may provide therapeutic benefit to treat such drug-resistant EGFR-mutant lung adenocarcinoma. However, such a strategy may not work for KRAS-mutant lung adenocarcinoma.

      TGFalpha (an EGFR ligand) promoted growth of EGFR-mutant lung tumors but not that of KRAS-mutant lung tumors in vivo. Importantly, the growth of EGFR-mutant lung tumors promoted by TGFalpha was accompanied by the expression of p63, which may suggest initiation of lung tumor lineage alteration from adenocarcinoma (p63 negative) to adenosquamous carcinoma (p63 positive).