Although an exogenous EGF is dispensable for EGFRL858R-mediated NIH3T3 cell transformation in vitro (Greulich et al., PLoS Med 2005), an exogenous EGF promotes growth of H1650 and H1975 lung adenocarcinoma cells that carry EGFR mutations in vitro (Sordella et al., Science 2004). However, it is unknown whether an exogenous EGFR ligand plays a role in growth of EGFR-mutant lung tumors in vivo. Here, using conditional transgenic mice expressing EGFRL858R or KRASG12D along with an exogenous TGFalpha (an EGFR ligand) in lung epithelium, we sought to determine the role of an EGFR ligand in EGFRL858R-lung tumors or wild type EGFR-lung tumors (KRASG12D-lung tumors) in vivo. As previously reported, conditional expression of TGFalpha (an EGFR ligand) in lung epithelium caused pulmonary fibrosis but not lung tumors (Korfhagen et al., J Clin Invest 1994; Hardie et al., AJP-LCMP 2004), indicating that the expression of an exogenous EGFR ligand is not sufficient to induce lung tumors. Conditional expression of EGFRL858R or KRASG12D in lung epithelium caused lung tumors as previously reported (Fisher et al., Genes Dev 2001; Politi et al., Gene Dev 2006). In our study using a new rtTA driver, Scgb1a1-rtTA line 2 (Perl et al., AJRCMB 2006), the majority of EGFRL858R-lung tumors occurred in alveolar regions while KRASG12D-lung tumors occurred in both alveolar and airway regions. Importantly, co-expression of EGFRL858R along with TGFalpha in lung epithelium induced the growth of lung tumors in airway regions but not in alveolar regions while the expression of EGFRL858R alone did not induce lung tumors in airway regions. Co-expression of EGFRL858R along with TGFalpha also shortened survival of the mice compared to the expression of either EGFRL858R or TGFalpha alone (median 32 days for EGFRL858R/TGFalpha vs 118 days for EGFRL858R alone or 248 days for TGFalpha alone). Co-expression of KRASG12D with TGFalpha did not influence tumor location or survival of the mice compared to the expression of either KRASG12D or TGFalpha alone. Consistent with the mouse study, TGFalpha expression in human EGFR-mutant lung cancer but not wild-type EGFR lung cancer was associated with worse overall survival (median 44 months for TGFalpha high vs 75 months for TGFalpha low; p<0.05) and recurrence free survival (median 21 months for TGFalpha high vs 61 months for TGFalpha low; p<0.05). Collectively, our results demonstrate that TGFalpha (an EGFR ligand) promotes not only the growth of EGFRL858R-lung tumors but also influences the regions where the EGFRL858R-lung tumors form.

Citation Format: Koichi Tomoshige, Yutaka Maeda. TGFalpha (an EGFR ligand) promotes growth of EGFR-mutant lung tumors in airway regions but not in alveolar regions in a transgenic mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1838. doi:10.1158/1538-7445.AM2017-1838