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Pulmonary adenocarcinoma (PAC) is the most common type of human lung cancer. A diagnosis of PAC, history of non-smoking, and presence of mutations in the EGFR are predictive factors for responsiveness of lung cancer to EGFR-specific tyrosine kinase inhibitors. The non-responsiveness of PACs in smokers suggests that pathways other than the EGFR regulate these cancers. We analyzed by immunohistochemistry human tissue microarrays from PACs and normal lung as well as tissues from PACs induced by the tobacco-specific carcinogen NNK in hamsters. In addition, we harvested cells from bronchiolar small airway epithelium, NNK-induced PACs, preneoplastic lesions and alveolar cells by laser capture micro-dissection and analyzed the expression of signaling proteins associated with the beta-adrenergic (beta-AR) and EGFR pathways. We found, that a subset of human and the all of the NNK-induced hamster PACs simultaneously over expressed beta-adrenergic receptors and their downstream effectors, PKA, CREB and phospho-CREB as well as the EGFR and members of its associated signaling pathway. These findings are in accord with in vitro studies that have provided evidence for transactivation of the EGFR pathway by beta-adrenergic signaling in cell lines from human PACs and small airway epithelia. Our data suggest that a subset of PAC patients may benefit from combined treatment with agents that inhibit signaling molecules of both, the beta-AR and EGFR pathways.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]