In non small lung cancer, the expression of the transcription factor TTF-1/Nkx2.1 correlates with the presence of EGFR mutations, therefore TTF-1 /Nkx2.1 expression is used to optimize an EGFR testing strategy and to guide clinical treatment. We investigate the molecular mechanisms underlying the functional connection between EGFR and TTF-1/Nkx2.1 gene expression in lung adenocarcinoma. Using the H1975 cell line as a non-small cell lung cancer model system and short hairpin RNA, we have selected clones with TTF-1/Nkx2.1 silenced expression. We have found that Leucine-rich immunoglobulin repeats-1 (LRIG1) gene is a direct target of TTF-1/Nkx2.1 and the transcription factor binding to the LRIG1 genomic sequence inhibits its gene expression. In TTF-1/Nkx2.1 depleted clones, we have found high levels of LRIGI and decreased presence of EGFR protein. Furthermore, in TTF-1/Nkx2.1 depleted clones we detected a reduced beta-catenin level and we provide experimental evidence indicating that TTF-1/Nkx2.1 gene expression is regulated by beta-catenin. Published studies indicate that LRIG1 triggers EGFR degradation and that mutated EGFR induces beta-catenin activity. Hence, with the present study we show that mutated EGFR, enhancing beta-catenin, stimulates TTF-1/Nkx2.1 gene expression and, at the same time, TTF-1/Nkx2.1, down-regulating LRIG1, sustains EGFR pathway. Therefore, LRIGI and beta-catenin mediate the functional connection between TTF-1/Nkx2.1 and mutated EGFR. (C) 2018 Elsevier Inc. All rights reserved.