Cigarette Smoke Induces Aberrant EGF Receptor Activation That Mediates Lung Cancer Development and Resistance to Tyrosine Kinase Inhibitors

Abstract

The EGF receptor (EGFR) and its downstream signaling are implicated in lung cancer development. Therefore, much effort was spent in developing specific tyrosine kinase inhibitors (TKI) that bind to the EGFR ATP-pocket, blocking EGFR phosphorylation/signaling. Clinical use of TKIs is effective in a subset of lung cancers with mutations in the EGFR kinase domain, rendering the receptor highly susceptible to TKIs. However, these benefits are limited, and emergence of additional EGFR mutations usually results in TKI resistance and disease progression. Previously, we showed one mechanism linking cigarette smoke to EGFR-driven lung cancer. Specifically, exposure of lung epithelial cells to cigarette smoke-induced oxidative stress stimulates aberrant EGFR phosphorylation/activation with impaired receptor ubiquitination/degradation. The abnormal stabilization of the activated receptor leads to uncontrolled cell growth and tumorigenesis. Here, we describe for the first time a novel posttranslational mechanism of EGFR resistance to TKIs. Exposure of airway epithelial cells to cigarette smoke causes aberrant phosphorylation/activation of EGFR, resulting in a conformation that is different from that induced by the ligand EGF. Unlike EGF-activated EGFR, cigarette smoke-activated EGFR binds c-Src and caveolin-1 and does not undergo canonical dimerization. Importantly, the cigarette smoke-activated EGFR is not inhibited by TKIs (AG1478; erlotinib; gefitinib); in fact, the cigarette smoke exposure induces TKI-resistance even in the TKI-sensitive EGFR mutants. Our findings show that cigarette smoke exposure stimulates not only aberrant EGFR phosphorylation impairing receptor degradation, but also induces a different EGFR conformation and signaling that are resistant to TKIs. Together, these findings offer new insights into cigarette smoke-induced lung cancer development and TKI resistance.